PHARMACODYNAMIC ASPECTS OF MODES OF DRUG

ADMINISTRATION FOR OPTIMIZATION OF DRUG

THERAPY

Amnon Hoffman, David Stepensky

Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew

University of Jerusalem, P.O.B. 12065, Jerusalem 91120, Israel.

Fax: +972-2-6436246

Email: ahoffman@cc.huji.ac.il

Abstract:

Due to various pharmacodynamic properties such as the nonlinearity of the

concentration-effect relationship, activation of feedback homeostatic mechanisms, induction

of pharmacodynamic tolerance etc. administration of the same dose of drug by different

modes is expected to produce different outcomes. This review clarifies the theoretical and

practical aspects of the impact of different modes of drug administration on the magnitude of

response, and hence on therapy outcomes. It discusses how the interrelationship between the

pharmacodynamic properties and the drug input function affect the magnitude of response. To

demonstrate this special dimension of drug therapy, relevant pharmacodynamic data was

obtained for drugs with different therapeutic applications, including antibiotics, analgesics,

diuretics, anti-cancer, anti-ulcer, antiinflammatory, anti-hypertensive, lipid-lowering anti-

parkinsonian, and immunosuppressive drugs. These examples provide guidelines for

implementing the role of the mode of drug administration (including rate, schedule and route

of drug treatment) during drug development or optimization of drug therapy.

Keywords: pharmacodynamics, pharmacokinetics, mode of drug administration, delayed

action preparations, tolerance.

2

1. Introduction

The technological, physicochemical and engineering knowledge for the development of

drug delivery systems has now reached the stage where it provides a very wide selection of

routes, sites, modes and rates of administration of a drug. To use these capabilities rationally,

it is necessary to determine the optimum input pattern of the drug (in terms of efficacy, safety,

convenience and economics) for a particular indication and target population.

By now, it has been established that the development of a drug delivery system (DDS)

should comply with pharmacokinetic considerations, including aspects of absorption,

presystemic biotransformation, distribution, systemic elimination and metabolic fate. In

general, the development of DDS was based on a simplified assumption of a direct

relationship between drug concentration in the blood and magnitude of response.

Accordingly, the basic philosophy behind the development of sustained release (SR)

formulations is to reduce fluctuation in drug response by minimizing fluctuations in systemic

drug concentrations. However, in most cases, the concentration-effect relationship (i.e.

pharmacodynamics) is non-linear. Thus, similar magnitude of fluctuations in drug

concentration at different concentration ranges are likely to cause dissimilar fluctuations in

the magnitude of response.1,2 Consequently, the input function may affect profoundly the

magnitude of drug effect(s) and has to be taken into consideration for optimization of drug

treatment.

2. The pharmacodynamic profile

2.1 Relationship between fluctuation in drug concentrations and

magnitude of response

The mathematical correlation between drug concentration (C) and the intensity of effect

(E) is most commonly described by sigmoid Emax model (see Figure 1):

nn

n

0 CCCmax

50

+ Ε ⋅ Ε

+ Ε = Ε

where E0 is the baseline effect, Emax, the maximal effect, EC50, the drug concentration that

elicits 50% of the maximal effect (i.e., the measure of drug potency), and n, shape factor

which determines the slope of the curve. The value of n has no clear physiological meaning,

but it is thought to evolve from the heterogeneity of concentration-effect properties of the

3

individual effector units (such as individual effector cells or channels).3

Different concentration ranges along the pharmacodynamic profile are shown in Figure

1. It can be seen that a certain degree of fluctuation in drug concentration (∆C) at different

zones elicit different degrees of change in magnitude of drug effect (∆E).2 Alterations in drug

concentration within E0 zone or Emax zone do not affect the magnitude of drug effect. Within

EC50 zone, ∆E is directly proportional to ∆C (or more specifically to ln∆C). In contrast,

fluctuations in drug concentration in Low E zone and High E zone produce non-proportional

change in ∆E. For instance, for n=1 a two-fold increase in drug concentration produces an

80% increase of drug effect at low E zone, a 46% increase at the EC50 zone, and only a 10%

increase at high E zone.

The sigmoidicity of the pharmacodynamic profile has a profound influence on the

magnitude of ∆E/∆C and on the width of a specific concentration zone. Generally, when n <

1, a shallow pharmacodynamic profile is observed resulting in moderate attenuation in

magnitude of effect even for large degrees of ∆C. Consequently, a high increase in drug

concentrations is needed in order to proceed from the minimal to maximal extent of drug

effects. For such a pharmacodynamic profile, SR formulations that minimize fluctuations in

drug concentration are less important. On the other hand, for n > 1, the resulting

pharmacodynamic curve is steep and is characterized by high affectability of response

intensity to a change in drug concentration. For n > 5 all-or-none response is observed and

small increment in drug concentrations near the EC50 region produces rise from E0 to Emax.

For these drugs the range between EC50 and the minimal concentration required to elicit Emax

(ECmax) is very narrow and it is extremely important to maintain drug concentration above

ECmax (e.g., levodopa – see specific section).

2.2 The impact of the rate of administration on the magnitude of

drug effect

The fact that pharmacokinetic processes are usually linear but in most cases the

concentration-effect relationship is nonlinear leads to profound impact of the drug input

function on the extent of the pharmacologic response. To illustrate this issue, a simulation of

pharmacokinetic and pharmacodynamic behavior of the drug following administration of the

same total dose at different rates was performed (Figure 2). The concentration vs. time

profiles were based on a one compartment model by applying bolus mode of drug

administration or constant infusion of the same total dose over 2, 4, 8 or 12 hours. The effect

vs. time data was produced by linking the concentration-time data to a sigmoidal Emax model

4

(Emax = 100% and EC50 = 0.05 mg/L) with different shapes (n = 0.5, 1, or 4). The impact of

different parameters on the magnitude of drug action may be estimated by comparing AUEC

values (area under effect curve) or by using an efficiency factor (EF = AUEC / AUC).4

The simulations show that the magnitude of effect is highly influenced by the rate of

drug administration. Prolongation of the administration time increases AUEC values by

several-fold. The magnitude of effect depends also on n value, particularly for lower rates of

drug administration. It can be seen that an increase in value of n from 1 to 4 increases the

effect (i.e., AUEC) by approximately 20% for the 4-h and the 8-h infusion regimens. The

opposite tendency occurs by prolongation of the infusion time to 12-h because Css values

drop below EC50 level.

Generally, the overall efficiency value of a certain mode of administration is a function

of the time that drug concentrations are maintained at the different concentration zones along

the pharmacodynamic curve. For the sigmoidal Emax model, maximum efficiency is

produced if the drug concentrations are continuously kept in the high E zone.4 Thus, for bolus

mode of administration relatively large AUC values can be associated with low AUEC value,

particularly if the peak drug concentrations happens to be several-fold higher than ECmax. In

this case, a sustained drug administration that prolongs the time spent over ECmax will

produce higher EF values (e.g., see section on beta-lactam antibiotics). On the other hand, if

Css value produced by continuous administratiis within the E0 zone, the overall efficiency

would be negligible in comparison to a bolus administration of the same dose.

It can be concluded that in most cases the magnitude of drug effect is dependent on the

mode of drug administration. The overall drug efficiency is dependent on the interrelationship

between several pharmacokinetic and pharmacodynamic parameters, including the dose and

rate of administration and the pharmacodynamic profile of the specific response. Simulations

showing the relationship between the drug dose and magnitude of drug effects in the sigmoid

Emax model were presented recently.5

3. Time-dependency of pharmacodynamic effects

It should be taken in account that temporal alterations in concentration-effect

relationship may occur, influencing the efficiency factor following drug administration.

Apparent time-dependency of the drugs pharmacodynamic parameters may result from a

delay between the pharmacokinetic and activity time course, or because of intrinsic alterations

of pharmacodynamic parameters.

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3.1 Hysteresis in the concentration-effect profile

In some cases, the pharmacologic response is delayed in relation to the kinetics of the

appearance of the drug in the blood and a counter-clockwise hysteresis is present in the

concentration-effect relationship.6 In certain cases, the reason for this outcome is a slow

equilibration between drug concentration in the systemic circulation and peripheral site(s) of

action. Consequently, a non-steady state effect-concentration relationship is produced, leading

to time-dependent changes in pharmacodynamic parameters. In order to elicit a certain

magnitude of effect, higher plasma concentrations are required at the beginning of drug

administration, and lower concentrations are needed once the drug is distributed to the

biophase. The magnitude of hysteresis is minimized by a slower rate of drug administration,

that reduces Cmax concentrations in the systemic circulation. Delayed response may also

result from the production of active metabolites, indirect pharmacodynamics due to time-

consuming signal transduction (accounting for delay between receptor binding and measured

effect), etc.

Several mathematical methods have been developed to overcome temporal discrepancy

in concentration-effect relationship and to estimate the intrinsic pharmacodynamic

parameters. Collapsing the hysteresis in the concentration-effect curve is a practical approach

that utilizes the indirect link model developed by Holford and Sheiner.7

3.2 Direct and indirect response

Discrepancy between the time courses of concentration and effect may be related to

indirect mechanism of drug action. This is true, for instance, when the observed drug response

is secondary to a previous, time consuming synthesis or degradation of endogenous bioactive

substance.8 Four basic pharmacodynamic models of indirect effects were developed by Jusko

et al, and were applied for numerous drugs, including hormones, diuretics, etc.9 Effect of the

drug input profile on the overall efficiency of drug effect in these indirect models have been

discussed thoroughly in recent review.4 In this work the concentration vs. time profiles of

low, medium and high drug doses were simulated for a one compartment model applying

bolus mode of drug administration or constant infusion over 6, 12, 24 or 72 hours. The

pharmacodynamic response was generated using four basic models of indirect effects (I-

inhibition of synthesis of endogenous substance, II-inhibition of degradation, III-stimulation

of synthesis, and IV-stimulation of degradation). The effect of the rate of administration and

6

drug dose on magnitude of pharmacologic effect is presented in Figure 3.4

It may be seen that slower rates of drug delivery improve the efficiency of the same

total dose. A maximal influence of the rate of drug delivery on the pharmacological response

was observed after the high dose. The influence of the infusion rate was the greatest for

Model II. While models I, III, and IV produced in a maximum of about 4-fold increase in

efficiency factor for continuous infusion compared to bolus mode of administration, model II

resulted in a 7-fold increase.

The results of the present simulation indicate that the pharmacodynamic efficiency is

dependent on the relationship between the target drug concentrations and IC50 values. For

relatively high drug doses, slower rates of drug delivery produce higher AUEC values and

comparable maximal effects (Emax). Further reduction in the rate of input lowers the

maximal effect, while higher AUEC values are attained. If additional attenuation in drug

release produces target concentrations that are below IC50, both maximal effect and

pharmacodynamic efficiency are reduced.

3.3 Tolerance phenomenon

The concentration-effect relationship of certain drugs is affected by continuous

exposure to the drug. Thus, due to changes that occur at the cellular level (such as gradual

reduction in the receptor density (down-regulation)), larger concentrations may be required to

maintain the same magnitude of effect over time, producing a tolerance phenomenon.

Evolvement of tolerance was observed for several drugs, including anticonvulsants, anti-

inflammatory drugs, amphetamines, barbiturates, benzodiazepines, caffeine, cocaine and

other CNS stimulating drugs, digitalis (heart failure), dopamine agonists, ethanol, indirectly

acting sympathomimetics, nicotine, organic nitrates, opiates, vasodilating drugs (heart

failure).10 It should be noted that if the pharmacologic responses of the drug are due to

interaction with different types of receptors, tolerance may develop for some, but not

necessarily for all drug effects. Magnitude of tolerance is related to the drug input function

(i.e., is time- and exposure-dependent) and is enhanced following slow drug input.11 In

general, the influence of the mode of administration is more substantial in the case of acute

tolerance development, such as in the case of organic nitrates (see specific section) which

indicates that SR mode of administration should be limited, and is less notable in those cases

where tolerance development is slow (e.g., levodopa - see specific section).

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3.4 Pharmacodynamic alterations due to activation of homeostatic

responses

Activity of many of the biochemical and physiological processes in the living body is

maintained within a certain limited range by means of feedback loop systems. In such a way

the body protects itself from drastic changes that would jeopardize the homeostasis. If the

homeostasis is altered due to pharmacological intervention, powerful feedback mechanisms

are activated, decreasing the magnitude of drug effect. The extent of activation of feedback

mechanisms is highly dependent on the rate of drug administration. While a bolus

administration may provoke counter activity, slow drug input may affect the body without

acute triggering of homeostatic responses.12

The ‘off response’ should also be taken into account for drugs that affect the body

homeostasis. Abrupt termination of drug input in such case may result in potentially

dangerous increase in drug effects (rebound activity). This phenomenon is specifically known

for antihypertensive drugs.13

4. Therapeutic and toxic effects

Almost all drugs possess multiple pharmacologic activities that are regarded as

therapeutic or side effects. It is important to understand that each of the pharmacologic effects

of the drug has its own pharmacodynamic profile. In order to optimize drug treatment the

pharmacodynamic profiles of both therapeutic and adverse drug effects should be taken into

account. As was discussed previously, for a particular pharmacodynamic profile, extent of

drug effect is profoundly dependent on the drug input function. Thus, optimization of drug

treatment must be applied to the differences in the pharmacodynamic profiles for different

drug effects, based on the knowledge of the drug’s pharmacodynamics, applying dosing

schedules with a higher ratio of resulting therapeutic/toxic effects.

In the case that different types of drug receptors are responsible for therapeutic and side

effects, selective activation/inhibition of receptors may be achieved by applying SR

formulations of the drug and producing a relatively narrow range of target drug

concentrations. General considerations concerning impact of mode of administration and dose

on selectivity of pharmacologic response were discussed recently by Hochhaus and

Derendorf.5

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5. Measurement of pharmacologic effect: The use of surrogate

endpoints as indices of therapeutic outcomes

In some cases, such as anti-cancer and immunosuppressive treatment (see specific

chapters), the magnitude of therapeutic effects and clinical outcome following the drug

treatment are not readily accessible. In this case, surrogate endpoints may be applied to

measure the biological activity and to adjust the treatment schedules. The optimal surrogate

endpoint should have the potential to yield unambiguous information about differential

treatment effects on the true endpoint. The relationship between surrogate marker and the

clinical outcome should be well established, both qualitatively and quantitatively, through

relevant epidemiological studies in order to estimate the expected clinical benefit. However,

the convenience of relying on biological markers on one hand and the substantial difficulties

in quantifying clinical end points and outcomes that are delayed in connection with changes in

the disease process, have led researchers to utilize surrogate markers, sometimes without

validation of their appropriateness. As noted recently by Colburn, although surrogate markers

can expedite the delivery of new therapeutic drugs to the market, if the marker is applied

inappropriately, it can prolong the development process and discourage their use.14 For

example, use of CD4 counts as surrogate markers for prolonged survival of patients with

human immunodeficiency virus (HIV), or reduction in premature ventricular contractions to

predict prolonged life expectancy have proven to be invalid.15,16

The issue of surrogate markers is raised here because in many cases they are being used

as a graded measure of pharmacological effect, which enables one to produce a reasonably

good pharmacokinetic/pharmacodynamic model of the kinetics of drug action. The important

issue is to clearly distinguish between those surrogate markers which are validated from those

that are associated with drug activity but do not provide sound indication about the real

clinical outcome.

6. From theory to practical examples: Pharmacodynamic

considerations in treatment of specific diseases

Controlled release (CR) dosage forms of medications have become relatively

prevalent in medicine today because of their ability to improve compliance and, perhaps, to

increase efficacy.17 CR formulations were developed according to the concept that ‘flatter is

better’, and formulation design tended to minimize fluctuations in drug blood concentrations.

9

As discussed above, this concept has many exceptions that evolve from the pharmacodynamic

characteristics of the drug and the mode of administration. The available information about

these factors is rather limited, and is only recently gaining momentum. In certain fields the

pharmacodynamic considerations have been thoroughly studied and have led to practical

modifications in mode of drug administration. For example, this has been seen in SR

nifedipine and other anti-hypertensive preparations, and hormonal therapy with gonadotropin

releasing hormone (GnRH). For other drugs, the available information about the impact of

mode of administration on magnitude of response (of both desired and adverse effects), and

hence, on therapy outcome, is scarce. In many cases, pharmacodynamic information that is

relevant for understanding the impact of the input function-response relationship is reported

indirectly or provides only partial or inconclusive knowledge. The goal of this review is to use

the available information in order to draw the picture of the influence of the mode of

administration on drug effect(s) in several clinical fields. Selected examples provide

guidelines for implementing this dimension of mode of drug administration (including rate,

schedule and route of drug treatment) during drug development or for optimization of drug

therapy.

7. Pharmacodynamics of antibacterial drugs

The major parameters used to quantify the effect of antimicrobial drugs are the minimal

inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC). Although

these parameters are good predictors of the potency of the drug-microorganism interaction,

they do not provide any information on the kinetics of action of the drug. For instance, the

MBC value does not provide information on the rate of bactericidal activity and whether this

rate can be enhanced by increasing antimicrobial concentrations. Similarly, MIC does not

provide any information about the persistent activity of the antimicrobial agent that remains

following exposure to the drug. These persistent effects include the postantibiotic effect

(PAE), postantibiotic sub-MIC effect (PAE_SME) and the postantibiotic leukocyte

enhancement (PALE).18 The degree of PAE and PAE_SME, that are very different for each

class of antimicrobial drugs (and for each specific drug-bacteria interaction), provide a better

understanding of the kinetics of drug action, thus furnishing a rational basis for determining

optimal dosage regimens for various human infections.

Antibiotics can be divided into three categories based on their pharmacodynamic

properties, including both their bactericidal activity and their persistent effects.19 The first

group of drugs (Category I) exhibits minimal concentration-dependent killing and produces

10

short term or no persistent effect with most bacteria. The killing rate of these antibiotics

saturates at concentrations of around four to five times the MBC. Thus, high concentrations

will not kill bacteria faster than lower concentrations. Furthermore, bacterial regrowth starts

very soon after serum and tissue concentrations fall below MIC. Penicillins, cephalosporins

and aztreonam exhibit this time course of antimicrobial activity. The second group (Category

II) is characterized by concentration-dependent killing over a wide range of concentrations,

and by prolonged persistent effects. The higher the drug concentration, the greater the rate and

extent of bacterial killing. This category includes aminoglycosides, fluoroquinolones and

metronidazole. Category III contains drugs such as vancomycin, clindamycin and macrolides

that demonstrate minimal concentration-dependent killing; however, they have prolonged

persisting effects.

7.1 Beta-lactam antibiotics (Category I)

7.1.1 Pharmacodynamic rationale for continuous adminis ration of beta-lactam

antibiotics

t

In vitro studies of the pharmacodynamics of beta-lactam antibiotics have shown that

killing of bacteria, in particular Gram-negative aerobic rods, is slow, time dependent, and

maximal at relative low concentrations.20 Further elevation of the dose is not associated with

increased bactericidal potency.21 It had been also suggested that at concentrations much

greater than the MIC a paradoxical pattern may occur, i.e., a decrease in bacterial kill

potency.22,23 These findings have led to the hypothesis that continuously maintained

concentrations above a certain level, related to the MIC for the specific pathogen, would be

more efficacious than the high peak and trough concentrations obtained with an intermittent

dosing regimen. Efficacy studies in laboratory animals are in agreement with these in vitro

findings. It was found that in order to obtain the same efficacy the daily doses have to be

eight-fold higher during intermittent infusion regimens than with continuous infusion.22

Other studies have shown that the percentage of survival of the animals increased linearly

with the frequency of dosing and time over the MIC but not with other pharmacodynamic

parameters.24 In addition to the preclinical findings, several clinical efficacy studies

corroborate this concept; however, these are still scarce. Schentag et al have shown a

significant relationship between time to eradication of Gram-negative pneumonia and time

over MIC.25 Weinstein et al examined the relationship between beta-lactam concentrations at

trough and the success of therapy in patients with acute and chronic osteomyelitis.26 It was

found that maximum efficacy with beta-lactam antibiotics in humans appeared to be

11

dependent on maintaining levels above the MIC of the infecting organism for the majority of

the dosage interval. The few randomized trials that have compared the efficacy of the beta-

lactams given by continuous infusion vs. intermittent administrations also support this

conclusion.

Exposures of staphylococci, streptococci or enterococci to different beta-lactams are

consistently followed by PAEs of several hours duration.21 This persistent suppression of

gram-positive cocci growth enabled the development of intermittent dosing regimens for

these drugs. Traditionally, intermittent intravenous infusions or intramuscular injections have

been considered to be the optimal dosing regimens that worked reasonably well in clinical

practice. However, due to the increasing number of immunocompromised patients, the rising

incidence of gram-negative infections, and the availability of improved intravenous drug

delivery systems, new strategies have been introduced for improving antimicrobial therapy

with beta-lactams. These strategies apply continuous infusions of these drugs to provide

improved patient outcome with reduced doses of drug.22

In summary, the goal of the dosage regimen of beta-lactam drugs should be to prevent

the drug-free interval between doses from being long enough for the bacterial pathogen to

resume growth.

7.1.2 Potential disadvantages associated with continuous administration of beta-

lactams

It is conceivable that if the infection is located at a site from which the antibiotic is

eliminated by a rate-limiting active transport, intermittent dosing would result in higher

concentrations at the site of infection than would continuous administration (e.g., infections in

the eye or cerebrospinal fluid). However, such a scenario is limited to a particular range of

antibiotic concentrations and then would apply only for those beta-lactams that are handled by

such mechanisms.24

Another situation is in a case where the antibiotic drug is eliminated from the site of

infection due to beta-lactamases, again with a rate-limiting step. For example, while an

antibiotic was diffusing to the center of an abscess, degradation by beta-lactamase-producing

bacteria could degrade it, thus producing antibiotic concentrations near zero during

continuous administration.

It was found that not all beta-lactam-bacteria interactions follow the rule of non-

concentration-killing efficacy dependency. For instance, Onyeji et al have showed that

cefaclor exhibited a marked inoculum effect against four pathogens studied, and that there

12

was concentration dependent killing at a large inoculum.27

With continuous infusion, a delay in drug equilibration to tissues occurs because of the

lag time required to reach effective steady state concentrations in serum. However,

administration of a loading dose prior to continuous administration would ensure the rapid

onset of antibacterial activity.

Another pharmacodynamic concern is a situation where continuous exposure to

antimicrobial concentrations is only slightly over the reported MIC. Thus, specific sub-

populations of resistant organisms that are typically not detected by MIC testing could grow.

Nevertheless, the development of resistance has not been found in any of the clinical trials

reported until now, probably because of the contributing activity of the immune system.

7.1.3 The target therapeutic concentration

Several investigators have proposed, based on in-vitro experiments, that a maximum

effect is reached at 4x MIC for the target bacterium.24 Preclinical investigation clarified that

the target ‘therapeutic concentration’ depends on the status of the immune system. For

example, serum ceftazidime concentration needed during continuous infusion to obtain 50%

efficacy in normal rats was between one-sixth and one-third the MIC, for the infecting K.

pneumoniae, depending on the severity of the infection. However, the concentration needed to

obtain 100% efficacy (ED100) was dependent not only on the severity of infection but also

whether the animals were leukopenic or not.24

7.1.4 The required time over MIC (T>MIC)

Craig has summarized all the available data from the literature that use mortality as an

endpoint and in which animals infected with S. pneumoniae were treated with penicillins or

cephalosporins.28 The duration of time that the serum level needs to be above the MIC to

ensure efficacy is shown in Figure 4. It can be seen that the mortality was virtually 100% if

serum levels were above MIC for 20% or less of the dosing interval. In contrast, as soon as

T>MIC was 40% - 50% of the dosing intervals or higher, bacteriologic efficacy was 90 to

100%. Similar results were found in clinical studies that assessed bacteriologic cure in otitis

media.29 The findings indicates that if serum levels are above the MIC for 40% to 50% of the

dosing interval, a bacteriologic cure of over 90% is obtained.

7.1.5 Parenteral versus oral therapy with beta-lactam antibiotics

13

The decision to use parenteral or oral therapy to treat an infectious disease has

traditionally depended primarily on the severity of the infection. It is often assumed that if the

patient with an infection is sick enough to be hospitalized, the patient is also sick enough to

receive parenteral antibiotics. The enhanced understanding of the concentration-activity of the

antibacterial efficacy has clarified that proper therapy can be achieved with oral

administration of antibiotic drugs. According to the rationale discussed above, the preferred

parenteral dosing strategy for therapy with beta-lactam antibiotics is continuous infusion.30

However, this approach has certain limitations, of which the most problematic issues are the

patient inconvenience due to decreased mobility, increased risk of bacteremia due to

intravenous line - infection, increased costs due to necessity for hospitalization and the need

for trained medical personnel for parenteral antibiotic administration. Oral therapy can replace

part of the parenteral antibiotic therapy.31 The major trend in oral beta-lactams has been to

find new drugs that have increased potency against gram-negative pathogens and longer half-

lives. However, several pharmaceutical approaches can also be used to prolong T > MIC. The

most obvious approach would be administration of larger doses that produces a longer

duration of T > MIC (as illustrated in Figure 5). This approach can be used for a beta-lactam

with elimination half life of 1 hr, such as penicillin V-K, that is an inexpensive drug, and

whose elevated concentrations are not associated with severe adverse reactions. However, a

considerably larger total daily dose is needed to achieve the same magnitude of T > MIC in

comparison to continuous administration.

Another approach to prolong T > MIC for beta-lactams is to develop an oral controlled

release formulation, which provide continuous administration of the drug from the gut to the

systemic blood circulation. Due to flip-flop pharmacokinetics of the sustained release

formulation, the apparent elimination half-life of the drug is extended. We have demonstrated

this approach with a hydrophilic matrix formulation of amoxicillin.32 This beta-lactam

antibiotic had pharmacokinetic properties that are similar to other drugs from this category,

including short elimination half life, and active absorption that is limited to the upper parts of

the gastrointestinal (GI) tract. Prolongation of T > MIC for these drugs following oral

administration (in vivo) is limited by the narrow absorption window.33 To overcome this

pharmacokinetic limitation the controlled release matrix tablet was designed to release 50% of

its content within 3 h, followed by a constant release rate for about 8 h.34 The rapid onset of

drug release was designed to provide an initial ‘loading dose’ and to maximize the absorption

phase in those parts of the intestine in which amoxicillin is actively absorbed by a carrier-

mediated process.35,36 The in vivo evaluation of the new formulation revealed that the extent of

absorption of the new formulation is not much different than that of a regular soft gelatin

14

capsule formulation. Furthermore, the time required to obtain therapeutic concentration (‘onset

time’) was found to be identical for the two formulations. However, T > MIC as well as T >

4.MIC of the drug against susceptible pathogens was found to be maintained for a significantly

longer period.

7.2 Pharmacodynamic rationale for pulse dosing of antibiotics with

concentration-dependent bacterial killing properties (Category II)

The drugs in this category are characterized by concentration-dependent killing over a

wide range of concentrations and by prolonged persistent effects. The goal of a dosage

regimen for these drugs is to maximize concentration. The magnitude of the peak level and

the AUC in relationship to MIC would be the important determinants of efficacy for these

drugs. Wide dosing intervals are also possible because these drugs induce prolonged PAE.

Sub-MIC concentrations and the presence of leukocytes can further prolong the PAE. These

preferred dosing strategy were found in-vitro and in preclinical studies and were partially

confirmed in clinical studies.

7.2.1 Pharmacodynamics of fluoroquinolones

The 24-hr AUC/MIC ratio is the parameter that best correlates with the efficacy of

fluoroquinolones as shown in Fig. 6.18,37 When tested for ciprofloxacin, this parameter was

better than the peak drug concentration and considerably better than T > MIC, which needed

to exceed the MIC for about 20% of the time interval to obtain any bacterial killing. In animal

infection models, the magnitude of the 24-hr AUC/MIC required to produce a bacteriostatic

effect is ~ 35.37 This value implies that the AUC averages ~ 1.5 times the MIC over 24 hr

period (i.e., 1.5 x 24 =36). This value is independent of the dosing interval, the

fluoroquinolones used, and the site of infection.18,38 It was found in experimental animal

infections and in clinical trails that the fluoroquinolones concentration in serum need on

average about 4 times the MIC in order to ensure bactericidal activity and patient cure. In vivo

preclinical studies confirmed the PAE of these drugs.

The development of the fluoroquinolones is considered to be the major advance over

the past decade in oral antimicrobial therapy due to their enhanced activity against gram-

negative bacilli. Twice a day dosing, by either oral dosing or intravenous administration

produce 24-hr AUC/MIC values that are considerably higher than 125 for various bacterial

species.

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7.2.2 Once a day aminoglycoside administration

There appears to be a general consensus that pulse dosing of aminoglycosides offers the

following advantages: i) relatively easy, straightforward initial dosing; ii) enhanced efficacy

due to higher peak levels; iii) enhanced safety due to shorter effective exposure time; iv)

convenience for both patients and nurses; v) likely on-time administration; vi) a much

reduced need for serum aminoglycoside levels monitoring (reduced cost); vii) facilitation of

drug administration through home care services (reduced cost).

While in preclinical investigations the 24-hr AUC/MIC ratio better correlated with

therapeutic efficacy than peak/MIC ratio, the opposite was found in the major clinical trials.39

To achieve a clinical response of >90% the peak concentration should exceed the MIC by 8–

10 fold. The once a day regimen that produces such elevated peak concentrations can also

reduce the rate of emergence of aminoglycoside-resistant mutants during therapy.40 This is

because the initial exposure of the microorganisms to aminoglycosides down-regulates

subsequent uptake of drug, thus higher MICs are exhibited for several hours.41 Therefore, the

larger time intervals that result from once-daily dosing regimen of the aminoglycosides enable

this effect to dissipate until next dosing. This, in addition to the prolonged PAE (2-8 hr) of

these drugs (which provide continued suppression of bacterial growth despite the decline of

the antimicrobial concentration to zero), augments the rationale for increased intervals

between doses (i.e. once daily vs. multiple daily dosage regimens).

The pharmacodynamics of aminoglycoside toxicity also corroborates once daily dosing

of these drugs. The mechanism of aminoglycoside nephrotoxicity involves an absorptive

influx at the proximal convoluted tubule cells that is mediated by a low affinity, high capacity

mechanism that can be saturable. Thus the uptake into the kidney is more efficient with low

sustained concentrations than with high intermittent concentrations. Several studies have

showed that the onset of nephrotoxicity is delayed for several days when the drug is

administered once daily.42 Animal studies that have examined ototoxicity show that the

degree of the cochlear damage is more related to the total daily dose of the aminoglycoside

rather than the frequency of administration. Hence, saturation of cochlear cells may play a

role in determining ototoxicity.43

Multiple meta-analysis studies that assessed the impact of mode of aminoglycoside

administration on therapeutic outcomes suggest a small, non significant trend towards better

efficacy and lower toxicity with once-daily regimen.44 However, it should be noted that not

in all situations once daily dosing would be a better choice than traditional intermittent dosing

regimens.43

16

7.3 Optimal dosing regimens of Category III antibiotics

The main pharmacodynamic parameter for drugs in this category is also the duration of

exposure. However, the relatively long elimination half-life together with persistent effects

allows drug levels to fall below the MIC for considerable portion of the dosage interval. Thus,

due to their unique pharmacokinetics and pharmacodynamics, the therapeutic outcomes

following therapy with these drugs is not affected by the mode of administration. For

instance, the optimal dosing method for vancomycin may be the one that achieves the lowest

AUC while concentrations are maintained above the MBC.45

7.4 Targeted antibiotic treatment by SR drug delivery systems: the

case of periodontitis

The clinical manifestation of periodontitis is the formation of a deeper space between

the teeth root surface and the opposing periodontal tissue. This crevice is termed a periodontal

pocket and its depth usually exceeds 5 mm. The anatomic configuration of the periodontal

pocket is an ideal habitat for microflora that is mainly composed of gram-negative bacteria

(mostly anaerobic). Collagenase and other enzyme that originate from the bacteria can destroy

the connective tissue of ligaments, while exotoxins evoke an inflammatory reaction. When

mechanically cleaning methods to improve oral hygiene fails, a chemotherapeutic approach

may be applied. Systemic administration has been useful in treating periodontal pockets, but

repeated, long term use of systemic antibiotics is fraught with potential danger including

resistant strains and superimposed infections. Therefore, the periodontal pocket is an excellent

example for localized infection site for which local administration of a drug by SR delivery

system provides an extremely useful solution. The important factor in the success of this

treatment is the ability to control and the release of the drug, thereby maintaining high intra-

pocket drug concentrations with very low plasma concentrations.

Intra-pocket delivery systems were found to be very effective clinically. The selection

of the antibiotic agent for these SR periodontal delivery systems has to be guided according to

the following principles. Since the amount of drug that can be placed in the periodontal

pocket is limited, the drug has to be highly specific against the periopathogenic bacteria. It

should not cause the development of resistant bacterial strains, and should not affect the soft

tissue of the pocket. So far, antiseptic agents, including chlorhexidine, cetylpyridinium

chloride and parabens on one hand, and antibiotics such as tetracycline, minocycline,

doxycyline, and metronidazole, on the other hand, have provided very effective control of the

periodontal microflora and significant reduction of the pocket depth (see Steinberg and

Friedman for a recent review46).

17

The same principles of local SR delivery of antibiotics that were noted above for the

treatment of periodontitis can be applied for other localized infections particularly for low-

perfused sites.

8. Anticancer drugs

Anticancer drugs are characterized by a low therapeutic index and a high extent of

intra- and inter-patient variability in pharmacokinetics and drug effects. Pharmacokinetic

studies indicate highly variable absorption, tissue distribution and elimination for most

anticancer drugs. Several–fold differences in drug clearances within a homogeneous patient

population have been observed for major anticancer drugs, including methotrexate, etoposide,

doxorubicin, cylophosphamide, etc.47 The extent of drug effects is also variable and depends

on mode of drug administration, tumor- and host-related factors. For certain tumors, the

chemosensitivity to certain agents is related to immunophenotype, tumor localization,

proliferative potential, and may be a subject to circadian variability.48,49 Figure 7 illustrates

variability in doxorubicin effect on human bladder tumors applying ex-vivo testing of drug

activity. In this study, a 35-fold variability in superficial bladder tumor chemosensitivity to

doxorubicin was observed, as opposed by only 4-fold variability in tissue pharmacokinetics.50

Thus, to optimize clinical outcome, the patient status should be assessed frequently and drug

dosing should be appropriately adjusted.

Choice of treatment regimens with anticancer drugs in most cases is based on

pharmacokinetic principles and clinical empiricism. This is mainly because the desired effect

(i.e., a reduction in tumor size or amount of tumor cells) is not readily detected and is not

applicable as a measure of clinical outcome. Generally, several types of pharmacokinetic or

pharmacodynamic markers can be applied for monitoring cancer patients. In certain cases, the

extent of main adverse effects (myelosuppression and gastrointestinal toxicity) appears to be

related to the systemic drug exposure, and monitoring of adverse effects may be applied for

adjustment of treatment protocols in the specific patient. It should be mentioned that a

temporal discrepancy exists between exposure time to the drug and the measured drug effects

and clinical outcome.

Anticancer drugs are seldom used as single therapy due to variability of tumor response

and elevated risk of emergence of resistance. When combination chemotherapy is applied,

pharmacodynamic relationships for individual anticancer drugs can’t be readily resolved.

Common use of support medications (i.e., antiemetic drugs, growth factors, protective agents,

etc.) and multiple courses of drug treatment further complicate the comparison between

18

different clinical settings and study of the drugs’ pharmacodynamic profile.

Due to the outlined reasons, little is known about the

pharmacokinetic/pharmacodynamic relationships of therapeutic or toxic responses of

anticancer drugs. Most pharmacokinetic/pharmacodynamic studies have focused on finding

correlations between the drug exposure and the extent of response following certain schedules

and modes of administration of the anticancer drug. Theoretical analysis suggests that the

pharmacodynamic profile of therapeutic response is related to the mechanism of action of a

specific drug, i.e. different profiles are expected for cell-cycle-specific or cell cycle-non-

specific anticancer drugs.51,52 If a drug’s cytotoxic activity is independent of cell growth

cycle (cell cycle-non-specific agents), a direct relationship is expected between the drug

exposure (i.e., AUC over a certain threshold concentration) and the response and the

sigmoidal Emax model may be used to describe the pharmacodynamic profile. In this case,

the total cytotoxic effect of a given dose of drug is independent of the schedule of

administration. This is not true for cell-cycle-specific agents whose mode of action is related

to the formation of active metabolites or accumulation of intracellular drug complexes. For

such drugs, the administration schedule may profoundly affect the extent of response. That is

because the response is mostly related to the duration of exposure above a threshold

concentration than to peak drug concentrations.

The goal of anticancer therapy is to produce the maximal therapeutic response while

producing acceptable toxicity. For a particular drug this may be accomplished by using the

difference between the pharmacodynamics of the therapeutic and toxic effects. The focus of

this review is mainly on optimization strategies of mono-therapy with selected anticancer

drugs, and on the impact of the mode of administration (dosing schedule, dose, and route of

administration) on the clinical outcomes.

8.1 Cell cycle-non-specific agents

8.1.1 Doxorubicin

The anthracycline doxorubicin is widely used in the treatment of both hematologic

malignancies and solid tumors. Doxorubicin is a cell cycle-non-specific agent, and the extent

of therapeutic response for a given dose should not be dependent on the schedule of

doxorubicin administration.52 However, doxorubicin cardiotoxicity appears to be

administration rate-dependent. A 24-hr infusion resulted in significantly higher cardiotoxic

effect in comparison to a 48- or 96-h infusion, whereas the incidence of myelosuppression

and mucositis were not affected.51,53 A once-weekly IV bolus administration schedule of

doxorubicin significantly reduces cardiotoxicity as compared with a once every 3 week

19

schedule but still does not affect the magnitude of the cytotoxic effect.54 Thus, the extent of

cardiotoxicity is related to the peak plasma concentrations, and more prolonged modes of

administration are needed to optimize the clinical outcome.

8.1.2 Platinum compounds

Cisplatin and carboplatin are cell cycle-non-specific agents widely used for treatment

of a variety of solid tumors. The major adverse effects of cisplatin are renal, neurologic and

ototoxic. A recent pharmacodynamic study by Nagai and Ogata showed that AUC values

highly correlate with cisplatin induced nephrotoxicity in rats.55 The maximum blood urea

nitrogen (BUN) level served as a marker of nephrotoxicity. The main results of the study are

presented in Figure 8. It may be concluded that an infusion mode of administration produced

2-3-fold less nephrotoxicity, compared to the effect of the same dose administered as bolus. In

addition, duration of exposure above a threshold concentration (AUC > Cmin) was shown to

be linked to the extent of nephrotoxic effect, irrespectively of dose and schedule (see Figure

9). Clinical studies in patients with various types of cancer showed that extent of

nephrotoxicity is mainly correlated with peak concentrations of cisplatin (Cmax),56 and that

slower administration rate results in lower incidence of gastrointestinal toxicity (emesis).57,58

Thus, for cisplatin, the extent of therapeutic activity is largely independent of mode of drug

administration, but continuous dosing schedule should be applied to reduce the incidence of

adverse effects.

The same considerations should apply for other platinum compounds, despite

somewhat different clinical profile. The toxicological properties of carboplatin differ from

that of cisplatin, and its primary dose-limiting toxicity is thrombocytopenia. A significant

relationship was found between area under the curve (AUC) and tumor response,

thrombocytopenia, and leukopenia in patients with advanced ovarian cancer.59 Circadian-

modulated treatment schedule of carboplatin showed no clinical advantage over flat infusion

in patients with advanced cancer.60 In contrast, a clinical study with another platinum

compound, oxaliplatin, showed lower incidence of neutropenia and vomiting in a circadian-

modulated mode of administration to carcinoma patients.

8.2 Cell-cycle-specific agents

8.2.1 Etoposide

Etoposide is cell-cycle-specific drug (late S and early G2 phases) which is highly active

in small-cell lung cancer and lymphoma. The schedule of etoposide administration profoundly

20

influences the extent of drug effects both in vitro and in vivo. Continuous exposure to low

levels of the drug was shown to produce enhanced therapeutic response in comparison to

bolus dosing. For instance, five consecutive daily 2-hr infusions produced partial remission in

89% of patients in comparison to a 10% response in a single 24-hour infusion of etoposide in

patients with small-cell lung cancer.61 The patient survival curve in this study is presented in

Figure 10. The AUC values were identical in the two arms of this study, but the duration of

exposure to low concentrations of drug ( > 1 mg/L) was doubled in the 5-day arm.

Several clinical studies showed that the hematological toxicity of etoposide is

correlated to the systemic drug exposure. For instance, in low-dose etoposide administered

orally to children with solid tumors, the time of exposure above a threshold concentration was

found to be more strongly correlated with neutropenia than other pharmacokinetic parameters,

including dosage and AUC.62 Antitumor activity is generally associated with the maintenance

of lower levels of etoposide than hematologic toxicity. Clark et al found that duration of

exposure to plasma etoposide > 3 mg/L is predictive of a nadir neutrophil count and > 2 mg/L

is predictive of a nadir WBC count.63 Then the same dose of etoposide was administered as 8

daily 75-minute infusions or 5 daily 2-hour infusions to patients with small-cell lung cancer,

higher hematologic toxicity was found for 5-day arm of the study due to prolonged periods of

time of higher exposure to etoposide.

In addition to schedule dependency of drug effects, clinical treatment with etoposide is

complicated by a high degree of inter-patient pharmacokinetic variability. Several clinical

conditions associated with elevated risk of adverse effects were identified, including patients

with impaired renal function, low serum albumin concentrations, or highly elevated liver

enzyme values.64 Thus, monitoring of drug concentrations as well as hematologic toxicity

should be applied for adjustment of etoposide doses in individual cancer patients as a means

to optimize the clinical outcome, in addition to applying a prolonged mode of etoposide

administration.

8.2.2 Fluorouracil (5-FU)

Fluorouracil is the agent of choice for treatment of colorectal cancer. Despite numerous

trials, the issue of schedule-dependency of 5-FU treatment remains controversial.65 Bolus

injection of 5-FU was shown to produce higher response rates and the same extent of toxic

effects in comparison to the same dose administered as short-term infusion (over 10-20

min).66,67 On the other hand, since 5-FU is a cell-cycle-specific antimetabolite agent,

prolonged exposure to this drug should result in 5-FU uptake by more tumor cells. Indeed, 48-

21

hr continuous infusion of 5-FU provided superior antimetabolic effect compared with bolus

administration in patients with gastric cancer as evidenced by higher extent of thymidylate

synthase (TS) inhibition in cancer cells.68 Although prolonged continuous infusion regimens

of 5-FU (over 24 hrs or more) were found to increase the response rate in comparison to bolus

injections, it did not improve the overall survival rate.69 This clinical outcome may be related

to difference in toxicity pattern produced by the different administration regimens.

In some patients tumor resistance evolves following bolus administration of 5-FU. In

this case continuous infusion of 5-FU may be applied to overcome the drug resistance.70

Administration of bolus injections and continuous infusion concomitantly or in alternating

order may serve as alternative strategy to improve the patient response.71

8.3 Optimization of anticancer treatment

Current treatment protocols of anticancer drugs do not provide optimal clinical

outcome in the terms of the response and the patient survival. In order to optimize the clinical

outcome, additional preclinical and clinical studies are needed to clarify the relationship

between the pharmacokinetic parameters and the therapeutic and toxic effects for individual

anticancer drugs. From the currently available data it seems that for cell cycle-non-specific

agents the magnitude of therapeutic drug effects is not related to the drug input rate. However,

the magnitude of adverse effects for such drugs may be significantly reduced by applying

prolonged modes of administration. For cell cycle-specific agents, prolonged mode of drug

administration should be applied to keep the drug concentrations within a certain

concentration range. This is because decrease in therapeutic effect occurs at lower

concentrations, while higher concentrations are associated with elevated magnitude of toxic

drug effects.

In addition to optimization of administration mode, profound pharmacokinetic and

pharmacodynamic variability of anticancer drugs requires application of individualized

treatment regimens for different cancer patients. Monitoring of plasma drug concentrations

may be applied to overcome the pharmacokinetic variability and to reach the target drug

exposure. However, this approach does not ensure that desired magnitude of drug effects is

attained. Monitoring of specific pharmacodynamic markers of tumor response or of toxic

effects has therefore a greater potential for reduction of inter-patient variability and for

optimization of dosing of anticancer agents.

9. Hormones: Pulsatile vs. continuous mode of administration

22

The input function of hormonal drugs is known to have a major impact on the

magnitude of therapeutic response. This phenomenon is related to physiological processes of

secretion and regulation of hormone levels in the body. Many hormones are secreted in

pulses, including insulin72,73 somatostatin, C-peptide, growth hormone (GH), PTH and

luteinizing hormone (LH). When the delivery system mimics the natural secretory pattern of

the hormone, it provides optimal hormone replacement therapy. On the other hand, the

continuous administration of large doses may suppress natural hormone secretion by

activating the feedback mechanisms in the body. Mazar has clearly described the effect of the

input function on the outcome of somatostatin derivative and for gonadotropin-releasing

hormone (GnRH).74 For somatostatin derivatives, optimal suppression of GH secretion in the

treatment of acromegaly, was obtained following a constant input rate. Similarly, if GnRH is

given continuously, gonadotropin secretion is suppressed through the mechanism of down-

regulation, which is used clinically in the treatment of prostate, endometrial and breast

cancer.75,76 On the other hand, pulsatile delivery of GnRH provides optimal response in

stimulating pituitary gonadotropin secretion. This particular response occurs because the

wave contour is a specific factor in the pharmacodynamic effects of GnRH on pituitary

gonadotropin and the steepness of the rising edge of the GnRH wave contour is a specific

determinant of pituitary LH secretion.77 In a like manner, continuous administration of

insulin down-regulates the numbers of insulin receptors, a phenomenon that can be minimized

by pulsatile insulin secretion.78

10. Anti-ulcer drugs

Current anti-ulcer treatment involves eradication the H. pylori infection by applying

antibiotic drugs, and concomitant suppression of acid secretion with H2-receptor antagonists,

or proton pump inhibitors (PPI). Since pharmacodynamic properties of the antibiotic drugs

were already discussed in the previous parts of this review, this chapter will concentrate on

the pharmacodynamic aspects of the antisecretory treatment.

The pathogenesis of acid peptic disorders, including gastric ulcers, duodenal ulcers, and

gastroesophageal reflux disease, involves an imbalance between acid secretion and gastric

mucosal defenses. The patterns of basal acid secretion in ulcer patients are similar to healthy

individuals (with the exception that ulcer patients secrete about 30% more acid) and follow a

circadian rhythm, with maximum acid secretion occuring during the early evening hours.79

The acid secretion activity is subject to high inter- and intra-patient variability; day-to-day

23

variation in the same individual can vary by more than 50%, obscuring the patient response to

anti-ulcer agent and distorting the relationship between plasma concentrations and

pharmacological response.80

It was generally accepted that ulcer healing is directly correlated to the degree of acid

suppression, and that a sustained reduction of gastrointestinal acidity (pH above 3) should be

achieved for optimal treatment results.81 Thus, the main pharmacologic approach of ulcer

healing involves decreasing of acid secretion by parietal cells using either histamine H2-

receptor antagonists, or proton pump inhibitors (PPI).

10.1 H2-receptor antagonists

H2-receptor antagonists were the most commonly prescribed agents for treatment of

peptic ulcer treatment, the main agents being cimetidine, ranitidine, and famotidine. These

drugs inhibit histamine-mediated gastric acid secretion and, thereby, produce incomplete

inhibition of acid secretion in response to meals because acid-secreting parietal cells continue

to receive stimulation via cholinergic and gastrin-mediated pathways.82 H2-receptor

antagonists may be administered via oral or intravenous routes. The duration of individual

drugs antisecretory action ranges from 6 to 12 hours.83

Repetitive dosing of H2-receptor antagonists results in rapid development of tolerance

(within several hours or days), reducing the drugs acid inhibitory effect.84 The apparent loss

of ranitidine efficacy was shown to occur within 12 hours in patients with gastric or duodenal

ulcers (see Figure 11).85 This phenomenon is thought to be mediated by the feedback

mechanisms elevating acid secretion by gastrin-mediated or alternate pathways, up-regulation

of H2-receptors, or decrease in proton pump turnover.86,87 Adverse effects are uncommon

with the H2-receptor antagonists and are generally mild.

10.1.1 Continuous vs. intermittent administration

Continuous infusions of H2-receptor antagonists were shown to maintain elevated

gastric pH for a significantly longer period of time than bolus regimens in ulcer patients,

critically ill patients, and in healthy volunteers.88-90 The gastric pH control could be achieved

at equal or lower total doses with continuous infusion.91 This apparent dose-sparing effect of

continuous mode of administration may be explained by relatively low ECmax (i.e., the

concentrations of H2-receptor antagonists that are needed to attain the maximal antisecretory

effect). Serum concentrations following bolus drug administration exceed this concentration

for a shorter period of the dosing interval than following continuous mode of administration.2

24

Additional explanation relates to the different degree of activation of tolerance-related

feedback mechanisms by bolus as opposed to continuous mode of administration. Continuous

exposure to lower doses of H2-receptor antagonists may provoke less feedback activation and

improved control of gastric acid secretion.

10.1.2 Circadian dependency

The dosing schedules of H2-receptor antagonists were considerably changed over time.

Long-term acid suppression was considered obligatory for ulcer healing, and the initial

approach applied multiple doses of H2-antagonists to reduce acid secretion for most periods of

the circadian cycle. Following this, a single daily night regimen of H2-receptor antagonists

was shown to produce better control of gastric pH compared to once-a-day morning

administration.92,93 This is because the intragastric contents are buffered by food during the

day, leading to lower apparent antisecretory effect following morning drug administration.

Inhibition of nocturnal acid secretion was considered of primary importance for ulcer healing,

and single bedtime dose had become the preferred regimen worldwide.

However, results of several clinical trials produced equivalent clinical outcome in terms

of ulcer healing of morning and bedtime doses of H2-antagonists, despite different control of

nocturnal acidity.94,95 Thus, nocturnal gastric acidity suppression is important but not

essential to promote duodenal ulcer healing. Currently, peaks of increased acidity are

considered the main factor hampering ulcer healing process, with no particular relevance to

which time of the circadian cycle during such peaks occur. Thus, efficient ulcer treatment

should prevent appearance of such peaks by implying sustained inhibition of parietal cell

activity.96

10.2 Acid (proton) pump inhibitors

The proton pump inhibitors (PPI) that were used in clinical settings include

omeprazole, lansoprazole and pantoprazole. Under strongly acidic conditions that exist in the

secretory canaliculi in the parietal cell, these drugs are converted to the active species

(sulphenamides) that irreversibly bind to the gastric proton pump (H+/K+-ATPase),

inactivating the proton transport. Thus, despite the short plasma half-life of 0.7-1.3 hours, this

covalent binding causes a prolonged duration of antisecretory effect, enabling a relatively

infrequent administration schedule.

Both oral and intravenous routes of administration of PPI were used in clinical practice.

The antisecretory effect is related to amount of the drug in the systemic circulation, and is

25

independent of the route of administration.80,97 Adverse effects occurred infrequently with

PPI agents and most commonly comprised transient gastrointestinal symptoms.

10.2.1 Administration schedule

Exposure to the relatively high doses of the drug may produce sufficient amounts of

active metabolite, which can inhibit acid secretion of actively functioning parietal cells.

However, the brief serum half-life of active metabolite may not last enough to affect other

populations of parietal cells that may be inactive at the time of administration. As a result,

populations of parietal cells that were not actively secreting acid during the time that the

active metabolite was in the serum become active afterwards and produce boots of low gastric

pH.98 Thus, the larger bolus dose provides small additional effect, and the degree of acid

inhibition increases gradually during the first days of once daily dosing because of an increase

in the number of H+/K+-ATPase enzymes inhibited (see Figure 12).80

In contrast to H2-receptor antagonists, continuous administration of PPI drugs does not

result in development of tolerance to the antisecretory effect (see Figure 11). Based on in vitro

studies, it was expected that continuous delivery of PPI drugs would inhibit more populations

of parietal cells and produce enhanced control of intragastric pH in comparison to bolus

doses.99 Intravenous administration of lansoprazole as bolus injection or infusion to healthy

volunteers was reported, however, to produce the same extent of antisecretory action.100,101

Nevertheless, these trials applied short-term (24-hour) intragastric pH monitoring and did not

necessarily represent the clinical outcomes in prolonged treatment of ulcer patients.

The higher efficiency of fractional administration of PPI drugs was confirmed in a

recent experiment when divided dosing of omeprazole provided superior gastric acid

suppression compared to once daily regimen in healthy volunteers.98 Additional studies

compared effectiveness of daily omeprazole administration with every other day or twice a

week schedules, with slightly improved clinical outcomes following once daily

administration.102-104

10.2.2 Circadian dependency

PPI drugs produce lower effects during the night than in daytime, independently of

administration time. Possible explanation to this phenomenon is that more proton pumps in

the parietal cells are activated by the repeated meal stimuli during the daytime, and become

prone to covalent binding of active metabolites, making the same dose of PPI drugs more

effective.103 Another contributing factor may be circadian dependency of the oral

26

bioavailability of the drug that yield higher plasma concentrations following morning

dosing.105,106

10.3 Optimization of anti-ulcer treatment

The concepts concerning role of overall amount of acid and relative importance of

acidity during different time intervals in ulcer pathogenesis have overcome major changes in

recent years. Currently, strong and continuous acid inhibition is not considered obligatory for

beneficial clinical outcome. Instead, short periods of elevated acidity in response to meals or

at night seem to be important pathophysiological events, whose control is sufficient to permit

quick ulcer healing.96 It seems that a small peak-preventing reduction of gastric acidity can

ensure the same therapeutic benefit as a strong and continuous acid inhibition, producing new

insights to optimized treatment regimen with antisecretory drugs.

Major pharmacokinetic and pharmacodynamic differences exist between the two

groups of antisecretory drugs, profoundly influencing the antisecretory treatment schedule.

For instance, the considerably shorter duration of action of H2-receptor antagonists in

comparison to proton pump inhibitors necessitates shorter administration intervals or

prolonged modes of administration.82 Pharmacodynamically, the antisecretory activity of H2-

receptor antagonists is weaker than that of PPI drugs (lower Emax), and decreases following

continuous exposure to the drug due to tolerance development that further reduces the drug

efficacy.84,107

As a consequence, the difference in ulcer healing rates between proton pump inhibitors

and H2-receptor antagonists103,108,109 may be attributed to different control of peaks of

elevated gastric acidity by clinically applied regimens of these drugs. Continuous modes of

administration of antisecretory drugs may provide better control of gastric acidity and

optimize clinical outcomes. For instance, continuous administration of H2-receptor

antagonists provides sustained reduction of gastric acidity and possibly prevents activation of

feedback mechanisms of acid secretion. As for proton pump inhibitors, continuous

administration may elevate treatment efficacy by increasing the number of inhibited H+/K+-

ATPase enzymes.

11. Controlled release systems in analgesia

Controlled release opioids have become well established in the management of pain,

particularly chronic cancer related pain, but also to alleviate non-cancer painful conditions

such as severe burns, surgery-induced pain, sickle-cell crisis and arthritis. While oral CR

27

morphine has predominated in this regard, other oral CR preparations have been developed

more recently, including codeine, dihydrocodeine, oxycodone and hydromorphone. In

addition, other dosage forms such as rectal morphine and transdermal fentanyl and

buprenorphine preparations have been developed for the same indications.

According to the World Health Organization recommendations, pharmacologic

treatment with morphine is considered the standard in alleviating moderate to severe pain

associated with neoplastic diseases.110 The drug can be administered via different modes and

routes, such as rapid input via multiple i.v. (or oral) bolus administrations, or in a sustained

manner by CR tablets or continuous infusion. Tolerance, manifested clinically as an increase

in the dose required over time to maintain a pain-free state, develops to the analgesic effect of

morphine.111 Despite the prevalence of this phenomenon, there is very limited quantitative

information on the rate and extent of tolerance development in humans. In particular, clinical

information is lacking about the relationship between mode of administration and the kinetics

of tolerance development. Preclinical studies in rats revealed that tolerance to morphine

antinociception developed rapidly within 8 to 12 hr during continuous i.v. infusion.112-114 A

longer period (7-10 days) is required for tolerance development during morphine

administration as multiple s.c. or i.p. bolus doses.115,116 Using a pharmacokinetic-

pharmacodynamic model that describes the development of tolerance in rats, Ouellet and

Pollack114 found that about the same degree of tolerance is achieved whether morphine is

administered as a continuous infusion or as intermittent i.v. boluses. This is because the half-

life for tolerance onset and offset is too long to allow significant sensitization between

intermittent doses. In their experimental model they showed that increasing the interval

between doses to one day does not reduce the magnitude of tolerance development during 13

days of morphine administration. This finding is in contrast to a previous report by Ekblom et

al,117 which used a similar modeling analysis to the continuous vs. bolus modes of morphine

administration. They concluded that when administering a bolus dose of morphine, the

antinociceptive effect is less influenced by the slow tolerance development than during

constant rate infusions. They observed rebound effects after cessation of the infusion but not

after the bolus dose. The half life of the tolerance development estimated in both studies was

long, between one to 3 days, that shows that tolerance develops slowly over several days.

Thus, it is not very clear if intermittent dosing reduces the degree of tolerance development,

and further pharmacokinetic/pharmacodynamic investigations are needed.

While the rationale for pursuing opioid pharmacokinetic/pharmacodynamic studies is

compelling, the complicating factors that hinder these investigations, especially in the clinical

setting, should be appreciated.118 These include: potential biases within analgesic studies,

28

that require double blind design; incorporation of the pharmacodynamics of the placebo

effect, that is known to be an inherent factor in the response to active treatments; opioid

receptors are located outside of the plasma compartment (the site of sampling), and different

opioid effects are likely to be mediated by receptors in different pharmacokinetic

compartments; metabolite activity may be of clinical importance; different concentration-

effect relationship for various pain intensity and pain characters; no stationary disease state;

development of acute and chronic tolerance; subjective methods of quantitative measurements

of pharmacodynamic effects.

11.1 Opioid analgesics

11.1.1 Controlled release formulations of morphine

The oral route is the preferred mode of morphine administration in cancer pain and the

majority of patients can be safely and effectively maintained by this route. The duration of

action after oral administration is short; therefore, if permanent relief of pain is required, the

drug has to be administered every 4 hr. For this reason, a sustained release formulation of

morphine could be very useful allowing a delay in the interval between the administrations,

from 6 times a day to twice a day, and even once daily.119 The efficacy of the marketed

formulation of CR morphine (MS-ContinR) has been demonstrated.120 The analgesic efficacy

of the CR formulations is not significantly different from that observed with reference

morphine syrup administered every 4 hr.

In addition to oral CR morphine formulations, many patients require an alternative

route of administration at some point in the course of their terminal illness. Common reasons

for the use of alternate route of morphine administration include severe nausea or vomiting,

dysphagia, bowel obstruction and severe confusion. Presently, the subcutaneous and rectal

routes represent the most widely used alternatives. The continuous subcutaneous infusion is

an effective procedure, but has certain disadvantages, including restriction of mobility and the

required frequent visits to the clinic for dosage adjustments and medication replenishment. An

improved approach is the CR morphine suppository formulations that demonstrates equivalent

pharmacokinetic and pharmacodynamic properties to the oral CR formulations.121

11.1.2 Other opioids CR formulations

Despite the extensive use of morphine, the occurrence of adverse effects necessitates

discontinuation in some patients. Clinicians treating cancer pain report significant variability

among patients in efficacy and side effects with available opioid analgesics. Patients who

29

have poor analgesic efficacy or safety outcomes with one opioid will frequently tolerate

another. This finding has led to the growing acceptance and clinical practice of opioid

rotation.122 The recent availability of opioid CR formulations such as oxycodone and

hydromorphone provides clinicians therapeutic options for cancer pain management.

Maddocks et al have shown that in patients with morphine-induced delirium, the substitution

of morphine with oxycodone results in significant improvement in the mental status, nausea

and vomiting.123 Recent evidence suggests that in addition to µ receptor-mediated analgesia,

oxycodone possesses intrinsic activity at the κ receptor, providing further rationale for its use

in treating patients unable to obtain an optimal analgesic or side effect profile with morphine

or hydromorphone.124

Oxycodone has been recently formulated into a 12 hr CR tablet which retains an onset

of analgesia as prompt as with conventional immediate-release oxycodone with majority of

patients reporting pain relief within 1 hr of administration and pain control throughout a 12-hr

period.125 The prompt onset of action results from the dual-release mechanism of the CR

delivery system. The rationale for this formulation is to avoid the need for concurrent

administration of an immediate release formulation that provide analgesia at the initial phase

after administration, until the CR formulation will constitute therapeutic concentration.

Another rationale that has been proposed for the biphasic opioid absorption profile is to

produce a peak-to-trough fluctuation comparable to conventional immediate release opioid.

This rationale is based on the suggestion, mentioned above, that very steady plasma opioid

concentrations may lead to tolerance development.117,126 The rapid onset of analgesic action

is also in accordance with the concept that have been proposed by Levy, that the rate of

decline of clinical analgesia after administration of various narcotic and non-narcotic

analgesics, and even placebos, is essentially the same, and the maximum degree of analgesia

and the duration of action is a function of Cmax.127 Thus, a rapid mode of administration that

provides larger Cmax values (that are not associated with significant adverse effects) could

provide a longer duration of pain relief than those obtained after a slower-absorbed dosage

form.

Pharmacodynamic evaluation of oxycodone revealed that minimal hysteresis occurred

between peak plasma oxycodone concentrations and peak pharmacodynamic effects,

indicating little or no delay in pharmacologic effect once oxycodone reached the systemic

circulation.118 In addition, it was found that a doubling of the dosage provided a doubling of

plasma oxycodone concentrations.128 These Cmax concentrations produced dose-related

differences in drug effect (measured with a 100 mm visual analog scale (VAS)), 40% and

60% respectively and remained sustained beyond 12 hr. The 20 mm difference in VAS drug

30

effect test is in the range reported with pain relief scales in relatively sensitive analgesic

studies with a doubling of opioid dosage, i.e., well beyond the linear portion of the log

concentration-response curve, where measurable changes in effect require dramatic changes

in opioid concentration at the receptor.118

A hydromorphone CR formulation that exhibited comparable analgesic efficacy to

oxycodone CR was associated with certain degree of hallucinations. There is extensive

clinical experience with the use of hydromorphone as an alternative to morphine. The

availability of CR formulations enables one to expand the use of this semi-synthetic congener

of morphine.

11.2 Nonopioid Analgesics

A key issue that should be taken into considerations in the pharmacodynamic rationale

to develop SR dosage forms for nonopioid analgesic drugs is the hypothesis (mentioned

above) that the analgesic effect depends on the peak blood concentration.129-131

Accordingly, the preferred mode of administration for these drugs would be by bolus (or

pulsatile) administration rather than a constant input at a slow rate. In many cases the data

support this theory. For instance, when the intensity of analgesic response to acetaminophen

was compared in mice following intravenous and subcutaneous injections, the analgesic effect

was greater after intravenous administration even at times when the blood levels after the

subcutaneous administration were higher.132 In addition, despite similar acetaminophen

plasma concentrations after short intravenous or continuous infusion, no significant analgesia

was detected after continuous infusion.133 Nielsen et al compared the efficacy of immediate

and slow release preparations of acetaminophen. Following administration of the SR tablets

the analgesic effect was lower and pain thresholds that were elevated 1 hr post-dose remained

relatively constant over the dosing interval.134 In another work, the same group found that the

acetaminophen SR preparation failed to produce any detectable analgesia.131 The hypothesis

is also supported by the data comparing the magnitude of analgesia induced by naproxen

versus naproxen sodium.135 The sodium salt that produced rapid absorption was associated

with more pronounced analgesic effect. In addition, it was found that the analgesic effect

produced by ibuprofen is stronger following soluble ibuprofen formulation that was

associated with faster absorption.136

It should be noted that beside this corroborating evidence that supports the hypothesis

of a link between the rate of decay of the analgesic effect and the peak concentration of the

analgesic compound, additional contradicting evidence exists. For instance, in a study

designed to compare the efficacy of intermittent with continuous administration of ketorolac

31

during the first 48 h after upper abdominal surgery, it was found that patients who received

the same rate of dosing of ketorolac as a continuous infusion instead of intermittent doses

showed a significant morphine sparing effect.137 Thus, more work is needed to further assess

the above mentioned hypothesis, which is a cornerstone for rationale development of

analgesic dosage for.

Another pharmacodynamic parameter that is relevant to optimizing drug formulation is

the ceiling effect detected for some of the nonopioid drugs. For instance, despite the linear

kinetics in serum drug concentrations following administration of ibuprofen 400 mg versus

800 mg, there were no differences in drug efficacy.

11.2.1 The anti-inflammatory activity of NSAIDs

11.2.1.1 Pharmacodynamic Rationale for Sustained Release formulations of NSAID anti-

inflammatory drugs

In contrast to the pharmacodynamic characteristics of the analgesic effect of NSAIDs,

superior suppression of platelet aggregation was attained following administration of a SR

preparation than following a single dose of rapid-release product.138 Similarly, it has been

shown that low concentrations of ibuprofen are required to maintain antiaggregatory activity,

which provide the rationale for a SR preparation of NSAIDs for this therapeutic goal.

11.2.1.2 Regional delivery to the site of anti-inflammatory action

The pharmacodynamic aspects of regional delivery of NSAIDs were assessed by

Martin et al in a preclinical investigation.139 They showed that direct administration of S-(+)-

ibuprofen into the site of inflammation (air pouch) produced the same concentration (at the

site of inflammation) effect relationship as intravenous administration of the drug. On the

other hand, an advantage following systemic rather than regional administration was revealed

for piroxicam, based on concentration-response analysis, indicating a major systemic anti-

inflammatory component for piroxicam but not for S-(+)-ibuprofen. These outcomes also

suggest that continuous administration of S-(+)-ibuprofen given either intravenously or via

the air-pouch, provided improved dose-response relationship in comparison to bolus

administration. This is probably because the initial exposure to high concentrations following

the bolus administration is less important than continuous exposure of the inflamed site to the

drug.

11.2.1.3 Differentiating between the effect of NSAIDs on cyclooxygenase isoforms

32

Cyclooxygenase (COX)-1 inhibition by NSAIDs is associated with gastrointestinal and

renal toxicity, while COX-2 inhibition has beneficial anti-inflammatory, analgesic and

antipyretic effects. The degree of selectivity of a given NSAID on the two distinct isoforms

COX-1 and COX-2 provide a convincing rationale for differentiating NSAIDs according to

their benefit/risk ratio. The concentration-response relationships established for the inhibition

of human COX-1 and COX-2 for meloxicam and naproxen was described recently by

Fenner.140 It was found that meloxicam inhibits COX-2 in human whole blood at

concentrations that are at least 10 times lower than those required to inhibit COX-1. In

contrast, the concentration-response curves for the inhibition of COX isoforms by naproxen

are close, suggesting approximately equipotent inhibition of COX-1 and COX-2. It is

expected that reduced fluctuations in blood concentrations due to utilization of SR

formulation for these drugs will produce higher degree of selectivity and less adverse effects

that result from the inhibition of COX-1. It could be important in view of the large inter-

subject variability in both pharmacokinetics and pharmacodynamics. Selective inhibition of

COX-2 may be achieved also applying selective COX-2 inhibitors (celecoxib and rofecoxib)

that have been marketed recently.

12. Direct administration of antiarrhythmia drugs to the heart

Conventional antiarrhythmia therapy with oral or intravenous administration is often

ineffective or results in toxic drug effects because of narrow therapeutic indices of most of

these agents. Due to the regional nature of cardiac disease it has been suggested to administer

antiarrhythmia drugs directly to the heart by localized cardiac delivery systems, based on

drug-polymer implants.141,142 This mode of administration may have several advantages,

including enhanced drug effects and reduced systemic drug toxicity. Since direct application

of the drug to the heart reduce the pharmacokinetic variability associated with absorption and

systemic disposition following conventional modes of administration, the efficacy and

toxicity would be more predicable.

The customary pharmacokinetic modeling approach cannot be used in this case, since

the heart cannot be grouped in the central compartment as drug delivered epicardially

accumulate into the heart muscle and produces a ‘depot’, from which the drug will equilibrate

slowly with various body compartments.

CR epicardial administration was tested preclinically with several drugs including

lidocaine, procainamide, verapamil and d-sotalol and proved to be safe and effective.141 For

instance, it was shown that when sotalol (a non-selective beta-blocker used for the treatment

33

of supraventricular and ventricular arrhythmias) was given by epicardial implants,

comparable myocardial concentrations of the drug were found in comparison to intravenous

administration but the total intravenous dose had to be considerably larger.142 Similarly, the

CR epicardial sotalol preparations produced electrophysiologic effects comparable to those

noted with intravenous administration at a significantly lower dose. This CR epicardial drug

delivery approach enables simple and direct ‘targeting’ of the drug to its site of action.

Thereby, it widens the therapeutic window of the drug by considerably increasing the margins

between therapeutic concentrations ‘seen’ by the target tissue and the systemic concentrations

that are associated with toxicity.

13. The antihypertensive effect of calcium antagonist drugs

13.1 The impact of rate of nifedipine administration on magnitude of

effect.

Nifedipine can be regarded as a classic example that illustrates the role of input rate on the

magnitude of effect. This calcium channel blocker has been used for several years in the

treatment of angina pectoris and hypertension. The drug was originally marketed in an

immediate release (IR) capsule formulation and later on in a sustained release tablet

formulation that had comparable bioavailability (50%). However, while the capsule produces

rapid and relatively high peak concentrations, the SR tablet gives a flat plasma concentration

profile. It was found that the increase in heart rate (side effect) was far less with the SR tablets

than with the IR capsules, whereas with both preparations a slight blood pressure lowering

effect was achieved in the normotensive subjects that were examined.143 This finding led to

the realization that the rate-of-increase in nifedipine plasma concentration (rather than the

absolute concentration) is a determining factor for the drug’s hemodynamic effects. Clear

evidence for this explanation was obtained in a study in which nifedipine was given by two

i.v. regimens designed to produce the same steady state concentration by a rapid vs. gradual

infusion rate. No increase in heart rate occurred with the slow regimen, whereas a substantial

and long lasting increase was seen with the rapid regimen.144 On the other hand, a gradual

decrease in blood pressure was observed following the slow input while blood pressure was

minimally affected. This outcome clarifies that the concentration-effect relationship of the

blood pressure lowering effect of nifedipine is shifted to the left and is steeper following a

slow input than with a rapid input rate as obtained following the administration of an IR

formulation. It has been proposed that following slow input, the activation of the

compensatory responses produced by high levels of endogenous agents such as

34

catecholamines is limited.145 Therefore, the tolerability of a SR formulation is likely to be

enhanced. There is evidence that the rate of input of nisoldipine plays a major role in its

hemodynamic activity profile,146 and it seems likely to be true for some other calcium

antagonists as well.147 These findings should not be regarded as surprising and should rather

be expected for vasodilator drugs.144,146

With a rapid decrease in peripheral vascular resistance, baroreflex activation, central

sympathetic activation and parasympathetic withdrawal serve to maintain blood pressure and

perfusion of vital organs. Heart rate and cardiac contractility increase, resulting in increased

cardiac output, and increased circulating catecholamines augment vascular resistance, that

blunts the direct drug effect. In contrast, slow drug input and gradual decrease in vascular

resistance limit this reflex activation and the direct drug effect can be more reliably observed.

13.2 Sustained release formulations as second generation of calcium

antagonists.

In order to minimize the disadvantages associated with rapid administration, and to

produce a constant plasma concentration for longer time intervals SR, extended release (ER)

and gastrointestinal therapeutic system (GITS) formulations were developed for various early

calcium antagonist medications including: nifedipine SR/GITS, nicardipine SR, verapamil

SR, and diltiazem SR, which forms the first subclass of the second generation of calcium

antagonists.148 The other subclasses comprises new dihydropyridines such as nisoldipine,

nitrenidipine, manidipine and others which posses improved pharmacodynamic and/or

pharmacokinetic properties including increased vascular selectivity.

A specific formulation developed to allow once-daily dosing of these drugs is a core

coated product, which claims equivalent efficacy to other SR formulations such as the GITS,

although the Food and Drug Administration does not consider the products to be

bioequivalent.149 The coat-core (CC) tablet consists of an external coat of slow release

nifedipine (or nisoldipine) and an internal core of rapid-release drug. The hemodynamic

effects of the long acting CC nisoldipine formulation appear to be similar to those of the

immediate release formulation, although differently timed.150

The availability of two different SR formulations of verapamil allowed some

interesting but inconclusive observations about the pharmacodynamics of the drug. Drug

pellets or beads have a much greater surface area than either tablets or caplet, which results in

faster drug release from the pellet formulation yielding a higher and earlier peak blood level,

with up to 40% increase in total bioavailability.151 However, no strong correlation exists

between blood levels and blood pressure response, at therapeutic concentrations. The data

35

suggests that once a ‘threshold level’ is reached with, verapamil higher doses and presumably

higher concentrations do not necessarily result in greater therapeutic response.152 This has

promoted the introduction of a 180-mg caplet that may represent such a ‘threshold’ dose since

its antihypertensive efficacy is similar to that of 240-mg verapamil.

13.3 The third generation calcium antagonists

The development of new molecules, including amlodipine and lacidipine, that can be

termed third generation calcium antagonists, has overcome most of the problems encountered

with the first and second generation products. Their unique characteristics are their interaction

with specific high affinity binding sites in the calcium channel complex and by the inherently

long duration of action. The lack of a clinically relevant increase in cardiac or peripheral

sympathetic activity, induced by an abrupt blood pressure reduction, is now recognized as

perhaps the most important feature of a drug of this class. However, it should be underlined

that this lack of autonomic activation does not abolish the minor vasodilator adverse events

such as flushing, headache and ankle edema that are still observed with these agents.153 The

inherently long half life (40 – 50 hr for amlodipine), and the high degree of lipophilicity,

allow their penetration deep into the lipid layer of the vascular cell membrane where the drug

is stored and slowly diffuses into a reservoir in the lipid bilayer where calcium channels are

situated.154 Therefore, it can be concluded that for these drugs no special SR formulations are

required.

14. Diuretics

14.1 General pharmacodynamic features

Diuretic drugs are commonly used for the treatment of heart failure or in hepatic, renal

or pulmonary disease when salt or water retention has resulted in edema or ascites. Several

groups of diuretic drugs are used clinically. Loop diuretics, especially furosemide, are the

most frequently prescribed and their clinical pharmacology is better understood.

The main therapeutic effects of diuretic drugs are water excretion (diuresis) and

natriuresis that are strongly interrelated. An apparent delay exists between the time of drug

administration and onset of diuretic effect. This delay may be partially attributed to

penetration of the drug to the site of action in the nephron in order to exert its therapeutic

activity. As a result, the magnitude of response is much better correlated to urine

concentration of diuretic drugs and not to the blood concentration and the pharmacodynamic

profile of diuretic drugs may be described applying a sigmoidal relationship between the

36

concentration of the diuretic in the urine and the extent of response.155,156 Since diuretic

drugs are characterized by indirect mechanism of action, their pharmacodynamics should be

more appropriately described applying indirect-response models. Recently such physiologic

indirect-response model was successfully applied to describe furosemide pharmacodynamics,

including development of tolerance to the diuretic effect following multiple dosing of the

drug.157

It was observed that the efficiency of the diuretic drug (i.e. ratio of diuretic

effect/systemic exposure) is not constant and varies profoundly with drug concentration and

time. Slow administration significantly increases the total diuretic effect per amount of drug

recovered in urine, and the cumulative diuretic effect may be highly influenced by the drug’s

administration profile.158 The extent of diuretic action is also subject to gender and age-

related inter-patient variability that may be attributed to alterations in drug metabolism,

disposition, or intrinsic diuretic responsiveness at the site of action.159,160 Diuretic efficiency

depends on additional, intra-patient factors, including development of tolerance and resistance

to drug effects. Thus, the extent of diuretic effect in specific patient is influenced by the mode

of drug administration.

14.2 Tolerance and resistance

There are two forms of diuretic tolerance: short-term and long-term. Short-term

tolerance refers to a decrease in the response to a diuretic drug following repetitive

administration. The exact mechanism by which short-term tolerance occurs is possibly related

to the activation of rapid homeostatic responses. Time course of tolerance development is

influenced by drug input rate, with slow continuous input producing less activation of

homeostatic mechanisms and elevating the overall diuretic and natriuretic effects.161 Fluid

and electrolyte replacement may prevent development of acute tolerance,162 and the results of

clinical trials applying different experimental protocols can’t be readily compared.163,164

The long-term administration of a loop diuretic leads to hypertrophy of distal nephron

segments due to unknown mechanisms. Consequently, sodium that is accumulated in the

urine in the proximal parts of nephron is reabsorbed at distal sites, leading to reduced drug

effects.165 This long-term tolerance to the loop diuretic may be partially prevented and

ameliorated by thiazide diuretic action on the distal parts of nephron. Thus, the combination

of a thiazide and a loop diuretic produces synergistic response and enhances the overall

diuretic efficiency.166

Certain clinical conditions may decrease the concentrations of the drug at the site of

action or sensitivity to the drug, producing so-called diuretic resistance. For instance, renal

37

insufficiency may decrease the delivery of the drug to the nephron and produce a

pharmacokinetic-related resistance to diuretics.167 Hepatic cirrhosis, on the other hand,

diminishes the diuretic response due to unknown pharmacodynamic mechanism, with no

effect on the amounts of diuretic drug that reach the site of action. Several other clinical

conditions (e.g., congestive heart failure and nephrotic syndrome) produce diuretic resistance

due to both pharmacokinetic and pharmacodynamic alterations.168

Several therapeutic strategies may be applied to overcome the tolerance and/or

resistance to the diuretic effect in specific clinical conditions. For loop diuretic drugs the main

strategies include changing the mode of administration or coadministration with thiazides.169

14.3 Loop diuretics

The clinically important pharmacokinetic features of loop diuretics are bioavailability

and half-life. On average, oral bioavailability of furosemide is 50 percent, but it ranges from

10 to 100 percent due to high inter- and intra-patient variability in drug absorption.170 This

wide range makes it difficult to predict how much furosemide will be absorbed in an

individual patient, and dose escalation must be applied before the drug is considered to be

ineffective. In contrast, absorption of bumetanide and torsemide is nearly complete, ranging

from 80 to 100 percent.

Loop diuretics are characterized by relatively short plasma half-lives ranging from one

hour for bumetanide to 3-4 hours for torsemide demanding frequent administration. When

short-acting diuretic preparations are applied (i.e., IV bolus or immediate release oral dosage

forms), a rapid and vigorous diuretic effect is produced for a period of up to several hours.

This rapid and excessive diuresis may cause side effects related to fluctuations in

intravascular volume and electrolyte imbalance. In addition, if the administration interval is

relatively large, the effect of a loop diuretic dissipates before the next dose is given. During

this time, the nephron can reabsorb sodium, resulting in so-called rebound sodium retention,

which may be sufficient to significantly diminish the prior natriuresis.157,171 Thus,

continuous exposure of nephron to the diuretic drug may attain higher diuretic effect with

lower risk of adverse effects.

14.3.1 Continuous intravenous infusion

In order to overcome the pharmacokinetic limitations and to prevent the development

of tolerance and resistance, a continuous intravenous infusion of loop diuretics can be applied.

Figure 13 shows that a 4 h infusion of azosemide produced higher diuretic effects in

38

comparison to IV bolus mode of administration of the same dose in rabbits.172

The superiority and better tolerability of IV infusion was confirmed in clinical studies

in patients with congestive heart failure and chronic renal insufficiency. Rudy et al gave the

same dose of bumetanide as two bolus doses separated by 6 hours or as 12-hour continuous

infusion to the patients with chronic renal insufficiency.173 The continuous infusion resulted

in significantly greater natriuretic effect (infusion, 236 ± 77 mmol, bolus, 188 ± 50 mmol, p =

0.01). The efficiency of diuretic effect for bolus and infusion modes of administration were

0.25 and 0.33 mmol/µg, respectively.

Additional advantage of continuous infusion of loop diuretics is the possibility of

gradual increase of infusion rate and accurate titration of the diuretic effect. Currently,

continuous IV infusion is widely used in clinical settings in severely ill patients, or in patients

refractory to conventional doses of loop diuretics.174 However, this mode of administration

can’t be applied in outpatient settings.

14.3.2 Sustained release formulations

The pharmacodynamic rationale of sustained input of the loop diuretics was applied for

development of sustained release (SR) dosage forms. Despite the lower bioavailability of SR

dosage forms due to limited absorption of furosemide in the distal parts of the gastrointestinal

tract, comparable diuretic effect was produced for the immediate release and SR dosage forms

of furosemide in healthy volunteers.175,176 This outcome is due to greater diuretic efficiency

for lower furosemide concentrations at the site of action (and consequently for lower drug

excretion rates), as shown in Figure 14. Thus, SR dosage forms produce prolonged exposure

of nephron to low furosemide concentrations that are associated with enhanced diuretic

efficacy.

The maximal extent of furosemide absorption is obtained in the stomach and upper

small intestine. Therefore, it was suggested that gastroretentive dosage forms of furosemide

are needed in order overcome the pharmacokinetic limitations of the drug absorption from SR

formulations.177 Several approaches to produce gastroretentive formulations of furosemide

were tested in animals178 and in human subjects179 producing encouraging results in terms of

enhanced efficiency, and reduced inter- and intra-patient variability of drug absorption.

However, despite the established pharmacokinetic and pharmacodynamic rationale,

gastroretentive dosage forms of diuretic drugs currently are not available in clinical settings.

39

14.4 Pharmacodynamic advantage of prolonged administration of

diuretic drugs

The pharmacodynamic profile of loop diuretics was extensively studied in animals and

in human patients. It was shown that prolonged continuous exposure to low drug

concentrations produces enhanced diuretic effects and is associated with reduced incidence of

adverse reactions.

Generally, prolonged kinetics of diuretic action may be achieved by several means.

One possibility is to use the drugs with relatively long pharmacokinetic half-life. However,

such drugs are not available clinically, and with currently used loop diuretics prolonged

effects may be achieved using continuous modes of administration. Continuous intravenous

infusion is commonly applied in intensive care settings, and sustained release dosage forms

may be used for peroral administration in outpatient settings.

Additional diuretic drugs may be preferably given by continuous modes of

administration. An example would be urodilatin, a polypeptide that is synthesized by the

kidney. Prolonged infusion of urodilatin lowers preload and increases diuresis and natriuresis

without neurohumoral activation or adverse side effects, and may be used as a powerful

diuretic agent in patients with congestive heart failure.180,181

15. Anti-hyperlipidemic drugs

Hypercholesterolemia plays a crucial role in the development of atherosclerotic

diseases in general and coronary heart disease in particular. The risk of progression of the

atherosclerotic process to coronary heart disease increases progressively with increasing

levels of total serum cholesterol or low-density lipoprotein (LDL) cholesterol at both the

individual and the population level. On the other hand, high plasma concentrations of high-

density lipoproteins (HDL) are associated with a reduced risk of coronary heart disease.

Drug therapy for hyperlipoproteinemia is initiated when other means including diet,

weight control, exercise and physical fitness program fail to achieve adequate results. The

drugs that are clinically used for the treatment of hyperlipoproteinemia can be divided into

two groups: compounds that lower triglyceride and cholesterol blood levels (i.e., nicotinic

acid (niacin), fibric acid derivatives), and compounds that mainly lower cholesterol levels

(anion exchange resins and hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors).

15.1 Niacin

Niacin is one of the oldest hypolipidemic drugs available, and has been in clinical use

40

for over 40 years. It is used to reduce cholesterol and triglyceride levels and, in particular, to

elevate HDL cholesterol levels. Although the drug can be regarded as relatively safe, niacin

therapy may be associated with certain adverse , some of which are directly related to the

mode of administration. Significant number of patients refrain from using this inexpensive

medication due to an intense cutaneous flush and pruritus that involve the face and the upper

part of the body. This flushing phenomenon is associated with the rapid onset of peak drug

concentration in the systemic blood circulation following oral administration of the immediate

release preparation. Continuous administration of the drug by means of SR formulations

produces a much slower rise in blood concentration and thereby reduces the flushing

phenomenon.182 On the other hand, SR formulations are far from being a simple solution

since this mode of administration produces constant exposure of the liver to relatively high

concentrations of the drug which have been reported to cause hepatotoxicity.182 However,

this severe adverse effect tends to be dose-dependent.183

The effect of mode of administration of low dose niacin on the magnitude of its

hypolipidemic effect was recently investigated in experimentally-induced hyperlipidemic

rats.182 It was found that continuous duodenal infusion, as well as SR tablets produced a

significantly larger magnitude of lipid lowering activity (reduction of both total cholesterol

and triglyceride levels) than bolus administration of the same doses. In addition, comparison

between the magnitude of lipid-lowering activity of continuous administration of the drug to

the gastrointestinal tract with equal intravenous infusion of the drug (same rate and dose)

indicated that there was no direct correlation between amounts of drug in the systemic

circulation and the magnitude of hypolipidemic response. Furthermore, no apparent effect

was detected after intravenous administration of the drug whereas continuous duodenal

administration significantly affected all three lipid components measured (cholesterol,

triglycerides and HDL serum levels). Another important finding of that investigation was that

there were no differences between the lipid lowering effects of niacin at 40 or 200 mg/kg.

This indicates that there is no apparent dose-response relationship, and no clear advantage of

higher dose of niacin. This finding is in agreement with clinical data showing that low dose

niacin (500 mg per day) produced effective lipid reduction in hyperlipidemic patients.184 The

outcomes suggest that administration of low dose niacin by an oral SR formulation will

enable safe and effective niacin therapy.

15.2 Bezafibrate

Bezafibrate is a fibric acid derivative that is used clinically to reduce blood lipoprotein

levels, especially triglycerides (TG), and elevate HDL cholesterol levels.185 On the basis of

41

pharmacokinetic rationale, specifically the relatively short biologic half life of the drug (1.5 to

2 hours), SR formulations of bezafibrate were designed and have been in clinical use during

the last decade. However, only recently, the pharmacodynamic aspects of this mode of

bezafibrate administration have been investigated.186 In that study, we assessed the role of

different routes and modes of administration of the drug on its hypolipidemic activity in three

models of experimentally-induced hyperlipidemia in rats. The work examined the hypothesis

that the major sites of bezafibrate action are located pre-systemically. Thus, continuous

administration of the drug to the GI tract is expected to augment its efficacy and provides a

pharmacodynamic rationale for an oral sustained release preparation of the drug. Indeed, the

results confirmed that equivalent doses of the drug produced significantly elevated

hypolipidemic activity when given at a slow rate directly to the GI tract compared to a PO

bolus and even to a slow IV infusion. In addition, administration of bezafibrate in a slow

release matrix tablet to the hyperlipidemic rats produced the same magnitude of effect as a

continuous duodenal infusion of the drug, thus proving the pharmacodynamic rationale for

this mode of administration for this drug. These preclinical experiments revealed lack of a

direct correlation between the systemic drug concentration and magnitude of effect. Lower

systemic drug concentrations, attained following ‘targeting’ of the drug from the gut to the

liver in a sustained manner, produced larger hypolipidemic responses in comparison to higher

systemic blood concentrations, and their respective effect, that were found following direct

administration of the drug to the systemic circulation.

It was discovered that bezafibrate undergoes a reabsorption process according to the

enterohepatic cycle. This enterohepatic cycle enhances the availability of the drug to the

presystemic sites of action (even following direct administration into the systemic blood

circulation), and is an important feature in the case of a drug like bezafibrate, and other anti-

lipid drugs, with a hepatic first pass dynamic response.

15.3 HMG-CoA reductase inhibitors

The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which

converts HMG-CoA to mevalonate. The liver is the target organ for the statins, since it is the

major site of cholesterol biosynthesis, lipoprotein production and LDL catabolism. However,

cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function, and

adverse effects of these drugs may be minimized by reduced systemic exposure to drug and

the active metabolite(s), especially during long term treatment. This can be achieved either by

specific degree of liver versus tissue selectivity of the drug and/or by targeting the drug to

their hepatic sites of action by oral SR formulation that presents the drug to the liver via the

portal veins in a sustained manner. An ideal dosing scheme would produce therapeutic levels

42

of the inhibitor to the liver at a rate that results in a hepatic extraction ratio that approaches

unity, thereby minimizing the systemic HMG-CoA reductase inhibitor levels.

McClelland et al investigated the cholesterol-lowering efficacy of an oral SR dosage

form of a potent HMG-CoA reductase inhibitor (water-soluble tromethamine salt of the 3-

hydroxyacid form of simvastatin) in comparison to bolus dosing of the drug.187 In that study,

dogs received the drug for 28 days once daily by oral bolus administrations (dry-filled

capsules) or by daily administration of an oral SR formulation (a controlled-porosity osmotic

pump). The observed mean AUC and Cmax after osmotic pump dosing were 67% and 16%

that of the bolus, respectively, while the maximum percentage decrease in serum cholesterol

was 34±8% for the SR formulation vs. 17±6% for the bolus. Combining the twofold

improvement in efficacy with the lowered systemic drug burden leads to 3- to 12-fold

‘therapeutic’ advantage from the controlled release dosage form.

The increased anti-lipid activity, taken together with the improved safety due to

reduced systemic exposure, indicate that SR formulations for these drugs may be

advantageous.

16. Levodopa therapy in Parkinson’s disease

Levodopa is the most effective treatment for Parkinson’s disease, but its efficacy is

hampered as the disease advances by clinical response modifications, namely motor

fluctuation and dyskinesias. As a result of its rapid intestinal absorption and metabolic

elimination, plasma levodopa concentration fluctuates widely in relation to each administered

dose from IR formulations. Early in the course of illness, no clear-cut relationship between

plasma levodopa profile and antiparkinson effect can be appreciated. With the progression of

the disease a correlation between levodopa plasma concentration and clinical effect

emerges,188 and in the more advanced stages the pattern of response mirrors the rapid rise

and fall in plasma levodopa concentrations after each dose (the ‘wearing-off’ phenomenon).

At this stage, the magnitude of drug effect is very sensitive even to small changes in drug

concentrations.189 Studies on the concentration-effect relationship of levodopa at this stage of

the disease demonstrated an immediate onset of the motor response when the plasma

concentration was exceeded and the appearance of off-reactions when plasma concentration

declined below this level. Controlled release preparations of the drug should provide

prolonged plasma concentrations above the ‘therapeutic’ threshold. However, fluctuations

were reported also with CR-preparations even when elevated plasma concentrations were

maintained. Harder et al investigated whether the concentration-effect relationship of

43

levodopa is influenced by the rate of drug absorption by comparing an IR and a CR

formulation.190 They found that both preparations produced the same maximal effect;

however, the estimated EC50 of levodopa were two fold higher for the CR formulation in

comparison to IR. The duration of action was approximately 1.5 longer for the CR

formulation. The gain in the duration of the motor response, which might be provided by

sustained plasma concentrations of levodopa following CR-preparation, was offset partially

by the apparent doubling of the threshold level (EC50).

The concept that rapidly changing plasma concentrations of levodopa are responsible

for the adverse effects of long-term levodopa therapy, have led to initiation of a 5-year

multicenter study that compared the efficacy and toxicity of SR vs. IR preparations of low

dose carbidopa-levodopa.191 It was found that the incidence of motor fluctuations was lower

than expected for both groups, probably due to the low dose used in this trial. In addition,

patients receiving SR preparations fared better on the activities of daily living portion of the

Unified Parkinson’s Disease Rating Scale and on portions of the Nottingham Health Profile.

Other clinical trials also exhibited somewhat better global evaluation for the levodopa CR

formulation in comparison to IR preparation.192,193

It should be noted that the oral absorption of levodopa is limited to a narrow absorption

window at the upper part of the GI tract, where absorption via active transport mechanism

takes place. Therefore, SR formulation that do not release most of its content during the first

6-8 hr after ingestion will release the drug in the colon where it will not be absorbed. The

preferred mode of administration of this drug is by gastroretentive dosage form that will

release the drug from the stomach into the duodenum in a sustained manner. Nonetheless,

such dosage form is not clinically available. In theory the best practical method to enable

constant plasma concentration of the drug would be by continuous intravenous infusion.

However, this mode of administration is not very feasible for long term use and it frequently

causes phlebitis. In addition, due to limited water solubility of the drug, large volumes have to

be infused over a day. For these reasons a new dosage form of levodopa in water dispersion

(DuodoapR) has been developed allowing the daily dose to be infused intraduodenally by a

portable pump.194 This route and form of administration have now been in use for several

years, with promising results.195 Paalzow and Sjalander-Brynne have assessed the outcome

of this mode of administration in individual patients.10 It was found that the plasma

concentration required to obtain satisfactory mobility decreased with time which indicate that

the sensitivity to the drug was elevated with time as indicated by reduced EC50 values. Since

all the patients were already on levodopa treatment for 6 to 20 years, it seems that the

improved efficacy found should be attributed to the individual titration of drug concentrations

44

for each patient together with the fact that following duodenal infusion they were not exposed

to high drug concentration (from absorption peaks). Furthermore, the fact that the infusions

were turned off during the night gave the body time to regain sensitivity, and reduce the

impact of tolerance development to the drug.

17. Antidiabetic drugs

It is well established that chronic hyperglycemia is associated with onset and

progression of diabetic complications, namely: microvascular complications, diabetic

ketoacidosis, and hyperosmolar coma. On the other hand, excessive glucose-lowering drug

regimens may produce life-threatening hypoglycemic episodes. Therefore, optimized diabetes

treatment will preserve the plasma glucose levels within the normal range throughout a 24-h

period applying appropriate mode of drug administration. In order to achieve this, physiologic

metabolic factors should be taken into account, including postprandial elevation of blood

glucose, in addition to the pharmacokinetic and pharmacodynamic properties of the specific

anti-diabetic drug. Several groups of drugs are used for diabetes treatment, including insulin

and its analogs, sulphonylurea drugs, metformin, and others.

17.1 Insulin

Insulin and its analogs have been used for several decades for treatment of diabetes

mellitus. Generally, a higher dose of insulin is associated with higher glucose-lowering effect,

and the sigmoid Emax model may be applied to describe the dose-response relationship.196

As seen in Figure 15, a temporal delay exists between the insulin blood concentrations and

glucose-lowering effect (resulting in counter-clockwise hysteresis) due to indirect mechanism

of insulin action and sustained penetration to the peripheral sites of action. The extent of

insulin effect is subject to inter- and intra-subject variability, and depends on administration

route, glucose blood level, liver function, and factors related to insulin resistance.197 Thus, in

order to reach appropriate glucose control in the individual patient, treatment regimen should

apply insulin analogs or formulations with different duration of action, and glucose blood

testing should be performed for dose adjustment in the initiation and throughout the treatment.

17.1.1 Physiology of insulin secretion

Insulin secretion from the pancreatic β-cells is pulsatile in nature and is regulated by

several feedback mechanisms related to glucose and insulin blood levels. Two types of

45

oscillations are recognized, with rapid pulses of approximately 10 min periodicity198 being

superimposed on much slower waves (every 50-100 min).199

It is not clear if mimicking of pulsatile pattern of insulin secretion is beneficial for

clinical outcome. In some trials, pulsatile intravenous administration of insulin to diabetes

patients was found to be more efficient than continuous delivery in reducing blood glucose,

lowering glucosuria, increasing insulin sensitivity and inhibiting lipolysis.200-202 However, a

number of clinical trials produced similar metabolic effects for pulsatile and continuous

modes of insulin administration.203-205 Variable degree of mimicking of insulin secretion

pattern in the individual studies (i.e., differences in pulse intervals and amplitude) may

explain the difference in metabolic outcomes. So far, pulsatile insulin delivery is rarely

applied in clinical practice and is mainly reserved for patients who are unable to attain the

tight glucose control through conventional means.206

17.1.2 Route of administration

The most common route of insulin administration remains subcutaneous injection.

Intraperitoneal insulin administration has been claimed to offer better glycemic control and

insulin sensitivity than subcutaneous insulin by producing a more ‘physiologic’ ratio between

portal and peripheral insulin concentrations. However, it was associated with enhanced liver

inactivation of insulin, reducing the peripheral effects and producing disadvantageous effect

on serum lipids.207,208

Despite considerable efforts, oral administration of insulin is not available clinically

due to rapid destruction of insulin in the gastrointestinal tract and limited absorption to the

systemic circulation. The benefits and limitations of alternative non-invasive routes of insulin

administration, including intranasal, inhaled, r, etc., are thoroughly discussed in recent

reviews.197,209-211

17.1.3 The administration schedule

The so-called ‘conventional’ treatment regimens have been used for most diabetic

patients. Their main advantages are simplicity, safety and ease of compliance for the patients,

but they can’t achieve perfect control of blood glucose. For more strict control of the blood

glucose levels, ‘intensive’ regimens were developed, requiring multiple injections of insulin

during the day to mimic the physiologic demands of insulin that are increased following

meals.

Continuous insulin infusion may provide improved glycemic control in patients that

46

still can produce their own insulin in response to postprandial hyperglycemia. Continuous

infusion produced improved metabolic effects compared to conventional insulin therapy in

diabetes patients,212,213 and in patients with diabetic ketoacidosis.214

Nighttime glucose control is difficult to achieve because of circadian variations in the

pharmacodynamics of insulin.215,216 The early morning requirement for insulin is twice as

much as the daytime demand and is related to alterations in cortisol and growth hormone

secretion.217 Therefore, the bedtime dose of either intermediate or long-acting insulin218 or

continuous insulin infusion may be applied to improve nocturnal glycemic control.219

17.1.4 Optimization of insulin treatment

The insulin requirement and sensitivity throughout the day depends on the metabolic

condition of the diabetes patient, and the pharmacokinetic and pharmacodynamic features of

the drug formulation. Current treatment protocols apply multiple daily glucose self-tests to

adjust the insulin doses and to prevent periods of excessive or insufficient hypoglycemic

activity. Various strategies applying novel insulin analogs, changing the dose, timing and the

route of the administration, were shown to improve, but not completely optimize glycemic

control in diabetic patients.

Further optimization of insulin treatment may be achieved using glucose-controlled

feedback (closed-loop) systems. Such a system consists of glucose sensor, insulin pump, and

pump control system and may simulate the physiologic release of insulin in order to reach the

target blood glucose concentrations. Currently, closed-loop systems may provide satisfactory

control of diabetes for over a year, with the major complication being obstruction of the

infusion catheter.220 In the future, the ultimate goal of diabetes treatment may be achieved by

restoring the feedback regulation of glucose homeostasis on the cellular level by implantation

of genetically-engineered β-cells with controlled insulin-releasing activity.

17.2 Sulphonylurea drugs

Sulphonylurea derivatives are hypoglycemic drugs frequently used in the treatment of

type 2 diabetes mellitus (NIDDM). The mechanism of action of sulphonylurea drugs involves

receptor-mediated blockade of ATP-sensitive potassium channels (KATP), that stimulate

insulin release by the pancreatic β cells and the contraction of vascular smooth muscle cells.

The later effect leads to impairment of the myocardial contractile function and exacerbation

of the myocardial ischemia, but the extent of its clinical relevance is still not clear.221,222

Different sulphonylurea derivatives may differ in their selectivity to

47

pancreatic/extrapancreatic effects.223

Additional adverse effects of sulphonylurea drugs are related to excessive blood

glucose reduction, leading to life-threatening hypoglycemic episodes, especially in elderly

patients. Short acting sulphonylurea drugs are clinically safer due to lower risk and duration

of such episodes.224 Continuous exposure of pancreatic β-cells to high concentrations of

sulphonylurea drugs induces down-regulation of β-cell sensitivity and development of

tolerance (i.e., reducing the extent of insulin-releasing effect).223,225

The dose-response relationship of sulphonylurea drugs is characterized by pronounced

interindividual variability. A recent study by Rydberg et al investigated concentration-effect

relationships for both glibenclamide and its metabolites after oral and intravenous

administration to healthy volunteers.226 Profound counterclockwise hysteresis was observed

following administration of the parent drug or the metabolites as a result of indirect

mechanism of hypoglycemic action of sulphonylurea drugs. The results of the study imply

that the major metabolites of glibenclamide possess a higher hypoglycemic activity at low

concentrations than the parent drug, contributing to prolonged duration of action following

glibenclamide administration.

The pharmacokinetic characteristics of specific sulphonylurea analogues or drug

formulations may be clinically relevant, determining the time to onset of action, magnitude

and duration of the glucose-lowering effect, and timing of drug administration in relation to

food intake. Immediate release preparations of short-acting sulphonylurea drugs may totally

abolish the meal-related elevation in plasma glucose when correct timing is achieved between

the mealtimes and the drug administration. On the other hand, sustained-release formulations

and longer-acting analogs provide prolonged hypoglycemic activity, but only partially

diminish the meal-related elevation in plasma glucose. In this case rapid-acting insulin

preparations are added to the treatment schedule to further reduce the fluctuations in blood

glucose levels.

Sulphonylurea therapy should always be initiated and maintained at the lowest possible

dose. This is because the use of high doses that are associated with elevated incidence of

cardiovascular and hypoglycemic adverse effects leads to diminished efficiency of anti-

diabetic treatment. On the other hand, prolonged exposure of the β cells to high doses of

sulphonylurea drugs may reduce the extent of desired effects due to development of

pharmacodynamic tolerance.

17.3 Metformin

Metformin is a biguanide antihyperglycemic agent widely used in the management of

48

type 2 diabetes mellitus (NIDDM). Metformin lacks a direct insulin-releasing effect. In the

diabetic state its main actions include antihyperglycemic, weight-stabilizing, lipid lowering,

and insulin-sensitizing effects. Unlike sulphonylurea drugs, metformin does not lower the

blood glucose below the normal levels in diabetics and, therefore, is safer in clinical use. The

mechanism of action of metformin is combined from several distinct effects in various organs

and tissues, including inhibition of gluconeogenesis in the liver, reduction of glucose

absorption, elevation of glucose metabolism in the intestine, and indirect inhibition of

lipolysis in adipose tissue.227

It seems that the multifactorial mechanism of action of metformin obscures the dose-

response relationship of the metabolic effects in individual organs and tissues and complicates

the optimization of metformin treatment. Generally, low metformin concentrations seem to

improve peripheral insulin resistance, and at higher concentrations a direct glycemia-lowering

effect occurs (mainly via inhibition of hepatic gluconeogenesis) leading to further reduction

of hyperglycemia.228

The overall metabolic effects of metformin seem to be concentration related.

Metformin concentrations were shown to be inversely correlated with serum triglycerides and

directly correlated with high density cholesterol (HDL), but not with metformin dose or

fasting plasma glucose.229 However, the same group of researchers found later that an inverse

correlation exists between metformin concentrations and plasma glucose levels. In addition, a

significant correlation was observed between mean plasma metformin concentrations and

mean plasma lactate levels.230

The overall extent of drug effects depends on the physiological and metabolic state of

the patient and the local tissue concentrations of the drug. However, the relative significance

of central and peripheral sites of metformin action to produce metabolic effects remains

unknown and seems to vary in different experimental conditions.227

We have shown that bolus administration of metformin to the small intestine provides

enhanced glucose-lowering effects in comparison to IV bolus administration of the equivalent

dose to streptozotocin-induced diabetic rats.231 This outcome is due to pharmacokinetic

differences between the two modes of administration. Following IV bolus, metformin is

extensively eliminated from the blood and concentrations rapidly drop below the therapeutic

window. Following oral or intra-intestinal administration, metformin accumulates in the

intestinal mucosa cells and is absorbed slowly to the systemic circulation.232 As a result, flip-

flop pharmacokinetic behavior is observed and therapeutic drug concentrations are kept for

prolonged period of time.

Accumulation of metformin in the intestinal mucosa produces a ‘natural’ sustained

49

release system. Due to this, similar magnitude of glucose-lowering effect is attained when

metformin is given intra-intestinally as bolus dose or continuous infusion.231 Thus, sustained

release of metformin in the gastrointestinal tract does not offer pharmacodynamic advantage

over immediate release formulations with respect to the hypoglycemic effect. However,

metformin accumulation in the intestinal mucosa apparently leads to gastrointestinal

intolerance, a very common adverse effect seen in up to 20% of patients.233 Gradual release

of metformin from CR formulations reduces the extent of accumulation and decreases the

incidence of gastrointestinal adverse effects. Results from clinical trials confirm the better

tolerability profile of CR formulations of metformin in comparison to regular dosage forms.

18. Optimal mode of organic nitrate administration

Organic nitrates are direct-acting vasodilators. They are metabolized by vascular

smooth muscle cells to form nitric oxide (NO). The NO then interacts with endogenous thiols

to form S-nitrothiol. Both NO and S-nitrothiol activates guanylate cyclase to produce cyclic

guanosine monophosphate which causes smooth muscle relaxation. The dilation of the venous

system results in a reduction of left ventricular end-systolic pressure and volume and

ultimately of oxygen consumption. Due to these activities, the organic nitrates were proved to

be effective agents in the management of acute episodes of angina pectoris and are

particularly useful in angina prophylaxis.

While the organic nitrates are extremely effective in prophylaxis, in acute therapy it

was found that continuous administration of these drugs by either oral or transdermal therapy

cause substantial attenuation of the antianginal effects. Thus, during acute therapy the organic

nitrates improve exercise tolerance for many hours, but during sustained therapy designed to

provide constant effective nitrate concentration throughout a 24-hr period there is significant

attenuation of the beneficial effects due to development of tolerance (for review see

Abrams234 and Elkayam235). Thus, steady-state nitrate levels are undesirable during

sustained therapy and therapeutic regimens must be developed to provide a low-nitrate period

during a significant portion of the 24 hr period.

These findings demonstrate clearly the necessity to consider the pharmacodynamic

properties of the drug during the development stages. Moreover, they emphasize the

important role of the mode of administration on the magnitude of response and the need to

assess the concentration-effect relationship characteristics over time. The initial development

of nitroglycerine (as well as other nitrates) SR formulations was based solely on a

pharmacokinetic approach. This approach concentrated on overcoming the short biological

50

half-life of the drug (several minutes for nitroglycerine), and maintaining steady state drug

concentrations over prolonged periods, that could be produced with various transdermal

formulations. This pharmacokinetic approach was based on the simplistic assumption that

constant blood concentration guarantees constant magnitude of response. The

pharmacodynamic information about the acute tolerance was found only after these products

were already on the market. These pharmacodynamic findings clarified the need for a drug-

free period for the vasculature to regain its reactivity toward organic nitrates. The drug free

period was found to be independent of drug formulation.

In conclusion, the ideal nitrate and formulation that can produce around-the-clock

protection against effort-induced angina is not yet available. When nitrates are used for

prophylaxis, differences in the pharmacokinetic properties of the different organic nitrates are

largely obviated by the SR pharmaceutical formulations, and there is no major

pharmacological reason to choose one nitrate over another. Several SR formulations,

including oral and transdermal products can provide objective anti-ischemic protection for

about 12 hr out of a day. The use of a drug free interval of 8-12 hr appears useful in avoiding

the development of pharmacological tolerance in some patients.236

19. Conclusions

The review furnishes insights into the important dimension of the input function of

drug administration. It draws a picture of the present available information in this area by

concentrating on relevant pharmacodynamic data that has been reported on drugs from

selected pharmacologic and therapeutic categories

This review highlights the important role of the mode of drug administration in

affecting the magnitude of response and thereby modifying the outcome of drug therapy. It

clarified the fact that in many cases the same dose of drug can produce very different

therapeutic outcome when administered by different modes of administration. It is important

to acknowledge this fact when comparing different pharmacotherapy protocols, especially

nowadays, when ‘evidence-based medicine’ (EBM) is becoming the rule in determining the

proper therapeutic protocol. This is because EBM, that is based on finding previous reports to

answer a specific clinical question, is mainly focused on the type of the drug and the dose

while paying not enough attention to the mode of drug administration. Moreover, this issue

should be emphasized for those scientists associated with performing meta-analysis of

randomized controlled clinical studies in order to determine optimized therapeutic guidelines.

In the last few years, there has been an increasing awareness of this subject and more

investigations that compare pulse dosing to sustained delivery of the drug have been reported.

51

In addition, further pharmacodynamic end points or surrogate markers that enable graded

measurement of effect are becoming available. Thus, it is foreseen that in the future,

pharmacodynamic aspects of drug delivery (that have been relatively ignored in the past) will

be incorporated together with the extensive knowledge that has been gained on the physical

aspects of drug delivery systems and the pharmacokinetic properties of drugs in order to

establish a sound rationale for optimized temporal patterns of drug therapy.

Acknowledgments:

Dr. Amnon Hoffman is affiliated with the David R. Bloom Center for Pharmacy.

52

Legends:

Figure 1: Illustration of distinct zones of concentration ranges along the sigmoid Emax

pharmacodynamic profile (from Hoffman,2 with permission).

Figure 2: Simulation of pharmacokinetic and pharmacodynamic behavior of the drug

following administration of the same total dose as IV bolus or constant infusion over 2, 4, 8 or

12 hours. The concentration vs. time profiles were based on a one compartment model, and

the effect vs. time data was produced applying sigmoid pharmacokinetic/pharmacodynamic

curves of different shape (n = 0.5, 1, or 4).

Figure 3: Simulation of area under the effect curve (AUEC) after administration of low ( ),

medium ( ), and high ( ) dose of the drug by bolus or continuous infusion modes of

administration for Models I, II, III, and IV of indirect drug response (from Gobburu and

Jusko,4 with permission).

Figure 4: Relationship between the time above the MIC and bacteriologic cure for various

beta-lactams against S. pneumoniae (O) and H. influenzae (∆) in patients with otitis media.

The solid and open symbols represent data obtained with penicillins and cephalosporins,

respectively (from Craig,28 with permission).

Figure 5: Effect of increasing the dose or changing the dosing regimen of a hypothetical drug

on peak/MIC ratio, AUC/MIC ratio, and duration of time that serum levels exceed the MIC

(from Craig and Andes, 38 with permission).

Figure 6: Relationship between the 24-hour AUC/MIC ratio of fluoroquinolones and survival

among animal models infected with a variety of gram-positive and gram-negative pathogens.

The solid and open circles represent data obtained in the thigh-infection model and in other

models, respectively (from Leggett et al, 37 with permission).

Figure 7: Inhibition of DNA precursor incorporation by doxorubicin. Human bladder tumor

histocultures were treated with doxorubicin for 2 h. Drug effect was measured as an inhibition

of the incorporation of BrdUrd. , average of all tumors; O, the most sensitive tumor; , the

most resistant tumor (from Gan et al,50 with permission).

53

Figure 8: Maximum BUN levels versus Cmax and AUC after single bolus injections ( ) and

3-h infusions ( ) of unchanged cisplatin (from Nagai and Ogata,55 with permission).

Figure 9: Relationship between AUC estimated by plasma concentration of unchanged

cisplatin greater than 0.9 µgPt/ml and maximum BUN level. O, Bolus injections; ∆, 3-h

infusion; , 2-h infusion; ∇, intermittent bolus injections (from Nagai and Ogata,55 with

permission).

Figure 10: Survival curve for patients treated with 24-hour continuous infusion and five-daily

infusions of etoposide (from Slevin et al,61 with permission).

Figure 11: Median percentage of time spent above pH thresholds of 4, 5.4, 6, and 6.8 during

the 2nd to 12th hour and the 13th to 24th hour with ranitidine or omeprazole in patients with

bleeding from either duodenal or gastric ulcer (* p < 0.003) (from Labenz et al,85 with

permission).

Figure 12: Median intragastric pH profile before and after the first and fifth daily morning

dose of omeprazole, 20 mg PO, 10 mg IV, and 40 mg IV (from Cederberg et al,80 with

permission).

Figure 13: Cumulative urine output and mean cumulative urinary excretion of sodium as

function of time following 1 min ( ) and 4 h (O) infusion of azosemide, 1 mg/kg, to rabbits

(from Park et al,172 with permission).

Figure 14: Diuretic efficiency (urine volume adjusted for basal diuresis per amount excreted

furosemide) vs. furosemide excretion rate following three 60 mg oral dosage forms during the

first 4 hr after dose ( plain tablets, Furix retard®, Lasix retard®) and from 4 to 24 h (- - -

). Arrows indicate direction of hysteresis (from Alvan et al,176 with permission).

Figure 15: Relationship of measured serum concentrations to the glucose infusion rate for

both regular and NPH insulin. Arrows indicate direction of hysteresis (from Woodworth et

al,196 with permission).

54

References:

(1) Levy, G., Bioavailability, clinical effectiveness and the public interest, Pharmacology, 8,

33-43, 1968.

(2) Hoffman, A., Pharmacodynamic aspects of sustained release preparations, Advanced

Drug Delivery Reviews, 33, 185-99, 1998.

(3) Hoffman, A. and Goldberger, A., The relationship between receptor-effector unit

heterogeneity and the shape of the concentration-effect profile: pharmacodynamic

implications, J Pharmacokinet Biopharm, 22(6), 449-68, 1994.

(4) Gobburu, J.V.S. and Jusko, W.J., Role of dosage regimen in controlling indirect

pharmacodynamic responses, Advanced Drug Delivery Reviews, 33(3), 221-33, 1998.

(5) Hochhaus, G. and Derendorf, H., Dose optimization based on pharmacokinetic-

pharmacodynamic modeling, in Handbook of Pharmacokinetic / Pharmacodynamic

Correlation, Derendorf, H. and Hochhaus, G., Eds., CRC Press, 1995, pp. 79-120.

(6) Danhof, M., Mandema, J.W. and Stijnen, A.M., Pharmacokinetic complexities of

pharmacodynamic studies in vivo, in The in vivo study of drug action: Principles and

applications of kinetic-dynamic modeling, van Boxtel, C.J., Holford, N.H.G. and Danhof, M.,

Eds, Elsevier Science, Amsterdam, 1992, pp. 29-58.

(7) Holford, N.H.G. and Sheiner, L.B., Kinetics of pharmacological response, Pharmacol

Ther, 16, 143-66, 1982.

(8) Jusko, W.J. and Ko, H.C., Physiologic indirect response models characterize diverse

types of pharmacodynamic effects, Clin Pharmacol Ther, 56(4), 406-19, 1994.

(9) Dayneka, N.L., Garg, V. and Jusko, W.J., Comparison of four basic models of indirect

pharmacodynamic responses, J Pharmacokinet Biopharm, 21(4), 457-78, 1993.

(10) Paalzow, L.K. and Sjalander-Brynne, L., Pharmacodynamic aspects of drug

administration. Tolerance development, Advanced Drug Delivery Reviews, 33, 235-40, 1998.

(11) Castaneda-Hernandez, G., Caille, G. and du Souich, P., Influence of drug formulation

on drug concentration-effect relationships, Clin Pharmacokinet, 26, 135-43, 1994.

(12) Hoffman, A., Shaked, I., Avramoff, A. and Golomb, G., Pharmacokinetics and

pharmacodynamics of trans-endometrial administered peptides and macromolecules,

Advanced Drug Delivery Reviews, 17, 191-203, 1995.

(13) Houston, M.C. and Hodge, R., Beta-adrenergic blocker withdrawal syndromes in

hypertension and other cardiovascular diseases, Am Heart J, 116, 515-23, 1988.

(14) Colburn, W.A., Selecting and validating biologic markers for drug development, J Clin

Pharmacol, 37, 355-62, 1997.

55

(15) Lagakos, S.W. and Hoth, D.F., Surrogate markers in AIDS: Where are we and where

are we going? Ann Intern Med, 116, 599-601, 1992.

(16) The Cardiac Arrhythmia Suppression Trial Investigators, Preliminary Report: Effect

of encainide and flecanide on mortality in a randomized trial of arrhythmia suppression after

myocardial infarction, N Engl J Med, 321, 406-12, 1989.

(17) Goldberg Arnold, R.J. and Kaniecki, D.J., Selection of oral controlled-release drugs:

A critical decision for the physician, South Med J, 86(2), 208-14, 1993.

(18) Craig, W.A., Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial

dosing of mice and men, Clin Infect Dis, 26, 1-12, 1998.

(19) Craig, W.A., Antibiotic selection factors and description of a hospital-based outpatient

antibiotic therapy program in the USA, Eur J Clin Microbiol Infect Dis, 14, 636-42, 1995.

(20) Vogelman, B. and Craig, W.A., Kinetics of antimicrobial activity, J Pediatr, 108, 835-

40, 1986.

(21) Craig, W.A. and Ebert, S., Killing and regrowth of bacteria in vitro: a review, Scand J

Infect Dis, 74 Suppl, 63-70, 1991.

(22) Craig, W.A. and Ebert, S.C., Continuous infusion of beta-lactam antibiotics,

Antimicrob Agents Chemother, 36, 2577-83, 1992.

(23) Holm, S., Odenholt, I. and Cars, O., Paradoxical effects of antibiotics, Scand J Infect

Dis, 74 Suppl, 113-7, 1991.

(24) Mouton, J.W. and Vinks, A., Is continuous infusion of beta-lactam antibiotics

worthwhile?-efficacy and pharmacokinetic considerations, J Antimicrob Chemother, 38, 5-15,

1996.

(25) Schentag, J.J., Smith, I.L., Swanson, D.J., DeAngelis, C., Fracasso, J.E. and Vari,

A., Role for dual individualization with cefmenoxime, Am J Med, 77, 43-50, 1984.

(26) Weinstein, M.P., Stratton, C.W., Hawley, H.B., Ackley, A. and Reller, L.B.,

Multicenter collaborative evaluation of a standardized serum bactericidal test as a predictor of

therapeutic efficacy in acute and chronic osteomyelitis, Am J Med, 83, 218-26, 1987.

(27) Onyeji, C.O., Nicolau, D.P., Nightingale, C.H. and Quintiliani, R., Optimal times

above MICs of ceftibuten and cefaclor in experimental intra-abdominal infections, Antimicrob

Agents Chemother, 38, 1112-7, 1994.

(28) Craig, W.A., Antimicrobial resistance issues of the future, Diagn Microbiol Infect Dis,

25, 213-7, 1996.

(29) Craig, W.A., The future - can we learn from the past?, Diagn Microbiol Infect Dis, 27,

49-53, 1997.

(30) Ronchera, C., Continuous infusion of beta-lactam antibiotics: a potential strategy to

improve parenteral antimicrobial therapy: A Consensus Document by the PharmPK List,

56

URL: www.cpb.uokhsc.edu/pkin/consensus/bl.html, access date - August 1999.

(31) Craig, W.A. and Andes, D.R., Parenteral versus oral antibiotic therapy, Med Clin North

Am, 79(3), 497-508, 1995.

(32) Hoffman, A., Danenberg, H.D., Katzhendler, I., Shuval, R., Gilhar, D. and

Friedman, M., Pharmacodynamic and pharmacokinetic rationales for the development of an

oral controlled-release amoxicillin dosage form, J Controlled Release, 54(Jun), 29-37, 1998.

(33) Barr, W., Zola, M., Candler, E., Shie-Ming, H., Tendolkar, A., Shamburek, R.,

Parker, B. and Hilty, M., Differential absorption of amoxicillin from the human small and

large intestine, Clin Pharmacol Ther, 56, 279-85, 1994.

(34) Katzhendler, I., Hoffman, A., Goldberger, A. and Friedman, M., Modeling of drug

release from erodible tablets, J Pharm Sci, 86(1), 110-5, 1997.

(35) Sinko, P.J. and Amidon, G.L., Characterization of the oral absorption of beta-lactam

antibiotics. II. Competitive absorption and peptide carrier specificity, J Pharm Sci, 78, 723-7,

1989.

(36) Torres-Molina, F., Peris-Ribera, J., Garcia-Carboneli, M., Aristorena, J. and Pla-

Delfina, J., Nonlinearities in amoxycillin pharmacokinetics. II absorption studies in the rat,

Biopharm Drug Dispos, 13, 39-53, 1992.

(37) Leggett, J.E., Fantin, B., Ebert, S., Totsuka, K., Vogelman, B., Calame, W., Mattie,

H. and Craig, W.A., Comparative antibiotic dose-effect relations at several dosing intervals

in murine pneumonitis and thigh-infection models, J Infect Dis, 159(2), 281-92, 1989.

(38) Craig, W.A. and Andes, D., Interrelationship between pharmacokinetics and

pharmacodynamics in determining dosage regimens for broad-spectrun cephalosporins, Diagn

Microbiol Infect Dis, 22, 89-96, 1998.

(39) Moore, R.D., Lietman, P.S. and Smith, C.R., Clinical response to aminoglycoside

therapy: importance of the ratio of peak concentration to minimal inhibitory concentration, J

Infect Dis, 155, 93-9, 1987.

(40) Blaser, J., Stone, B.B., Groner, M.C. and Zinner, S.H., Comparative study with

enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of

antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance,

Antimicrob Agents Chemother, 31, 1054-60, 1987.

(41) Daikos, G.L., Lolans, V.T. and Jackson, G.G., First-exposure adaptive resistance to

aminoglycoside antibiotics in vivo with meaning for optimal clinical use, Antimicrob Agents

Chemother, 35, 117-23, 1991.

(42) International Antimicrobial Therapy Cooperative Group of the European

Organization for Research and Treatment of Cancer, Efficacy and toxicity of single daily

doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime

57

for infection in patients with cancer and granulocytopenia, Ann Intern Med, 119, 584-93,

1993.

(43) Freeman, C.D., Nicolau, D.P., Belliveau, P.P. and Nightingale, C.H., Once-daily

dosing of aminoglycosides: review and reccomendations for clinical practice, J Antimicrob

Chemother, 39, 677-86, 1997.

(44) Gilbert, D.N., Editorial response: meta-analyses are no longer required for determining

the efficacy of single daily dosing of aminoglycosides, Clin Infect Dis, 24, 816-9, 1997.

(45) Dufful, S.B., Begg, E.J., Chambers, S.T. and Barclay, M.L., Efficacies of different

vancomycin dosing regimens against Staphylococcus aureus determined with a dynamic in

vitro model, Antimicrob Agents Chemother, 38(10), 2480-2, 1994.

(46) Steinberg, D. and Friedman, M., Dental drug delivery devices: local and sustained

release applications, Crit Rev Ther Drug Carrier Sys, in press, 1999.

(47) Galpin, A.J. and Evans, W.E., Therapeutic drug monitoring in cancer management,

Clin Chem, 39(11 Pt 2), 2419-30, 1993.

(48) Asselin, B.L., Evaluation of tumor cell heterogeneity based on response to

chemotherapy, Clin Chim Acta, 206(1-2), 33-44, 1992.

(49) Hrushesky, W.J., Circadian pharmacodynamics of anticancer therapies, Clin Chem,

39(11 Pt 2), 2413-8, 1993.

(50) Gan, Y., Wientjes, M.G., Badalament, R.A. and Au, J.L., Pharmacodynamics of

doxorubicin in human bladder tumors, Clin Cancer Res, 2(8), 1275-83, 1996.

(51) Powis, G., Anticancer drug pharmacodynamics, Cancer Chemother Pharmacol, 14(3),

177-83, 1985.

(52) Jusko, W.J., Pharmacodynamics of chemotherapeutic effects: dose-time-response

relationships for phase-nonspecific agents, J Pharm Sci, 60(6), 892-5, 1971.

(53) Kalns, J.E., Millenbaugh, N.J., Wientjes, M.G. and Au, J.L., Design and analysis of

in vitro antitumor pharmacodynamic studies, Cancer Res, 55(22), 5315-22, 1995.

(54) Lum, B.L., Svec, J.M. and Torti, F.M., Doxorubicin: alteration of dose scheduling as a

means of reducing cardiotoxicity, Drug Intell Clin Pharm, 19(4), 259-64, 1985.

(55) Nagai, N. and Ogata, H., Quantitative relationship between pharmacokinetics of

unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-

time curve (AUC) as the major toxicodynamic determinant in vivo, Cancer Chemother

Pharmacol, 40(1), 11-8, 1997.

(56) Nagai, N., Kinoshita, M., Ogata, H., Tsujino, D., Wada, Y., Someya, K., Ohno, T.,

Masuhara, K., Tanaka, Y., Kato, K., Nagai, H., Yokoyama, A. and Kurita, Y.,

Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after

intravenous infusions of cisplatin to cancer patients, Cancer Chemother Pharmacol, 39(1-2),

58

131-7, 1996.

(57) Jordan, N.S., Schauer, P.K., Schauer, A., Nightingale, C., Golub, G., Martin, R.S.

and Williams, H.M., The effect of administration rate on cisplatin-induced emesis, J Clin

Oncol, 3(4), 559-61, 1985.

(58) Reece, P.A., Stafford, I., Abbott, R.L., Anderson, C., Denham, J., Freeman, S.,

Morris, R.G., Gill, P.G. and Olweny, C.L., Two- versus 24-hour infusion of cisplatin:

pharmacokinetic considerations, J Clin Oncol, 7(2), 270-5, 1989.

(59) Jodrell, D.I., Egorin, M.J., Canetta, R.M., Langenberg, P., Goldbloom, E.P.,

Burroughs, J.N., Goodlow, J.L., Tan, S. and Wiltshaw, E., Relationships between

carboplatin exposure and tumor response and toxicity in patients with ovarian cancer, J Clin

Oncol, 10(4), 520-8, 1992.

(60) Natoli, C., Salini, V., Irtelli, L., Martino, M.T., Garufi, C., Grassadonia, A.,

Fiorentino, B. and Iacobelli, S., A phase I study of 5-day continuous venous infusion of

carboplatin at circadian rhythm-modulated rate compared with constant rate, Anticancer Res,

16(3a), 1275-9, 1996.

(61) Slevin, M.L., Clark, P.I., Joel, S.P., Malik, S., Osborne, R.J., Gregory, W.M., Lowe,

D.G., Reznek, R.H. and Wrigley, P.F., A randomized trial to evaluate the effect of schedule

on the activity of etoposide in small-cell lung cancer, J Clin Oncol, 7(9), 1333-40, 1989.

(62) Sonnichsen, D.S., Ribeiro, R.C., Luo, X., Mathew, P. and Relling, M.V.,

Pharmacokinetics and pharmacodynamics of 21-day continuous oral etoposide in pediatric

patients with solid tumors, Clin Pharmacol Ther, 58(1), 99-107, 1995.

(63) Clark, P.I., Slevin, M.L., Joel, S.P., Osborne, R.J., Talbot, D.I., Johnson, P.W.,

Reznek, R., Masud, T., Gregory, W. and Wrigley, P.F., A randomized trial of two

etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy

and toxicity, J Clin Oncol, 12(7), 1427-35, 1994.

(64) Joel, S.P., Shah, R. and Slevin, M.L., Etoposide dosage and pharmacodynamics,

Cancer Chemother Pharmacol, 34, S69-75, 1994.

(65) Kamm, Y.J., Wagener, D.J., Rietjens, I.M. and Punt, C.J., 5-Fluorouracil in

colorectal cancer: rationale and clinical results of frequently used schedules, Anticancer

Drugs, 9(5), 371-80, 1998.

(66) Larsson, P.A., Carlsson, G., Gustavsson, B., Graf, W. and Glimelius, B., Different

intravenous administration techniques for 5-fluorouracil. Pharmacokinetics and

pharmacodynamic effects, Acta Oncol, 35(2), 207-12, 1996.

(67) Glimelius, B., Jakobsen, A., Graf, W., Berglund, A., Gadeberg, C., Hansen, P.,

Kjaer, M., Brunsgaard, N., Sandberg, E., Lindberg, B., Sellstrom, H., Lorentz, T.,

Pahlman, L. and Gustavsson, B., Bolus injection (2-4 min) versus short-term (10-20 min)

59

infusion of 5-fluorouracil in patients with advanced colorectal cancer: a prospective

randomised trial. Nordic Gastrointestinal Tumour Adjuvant Therapy Group, Eur J Cancer,

34(5), 674-8, 1998.

(68) Tsujinaka, T., Kido, Y., Shiozaki, H., Iijima, S., Homma, T., Sakaue, M. and Mori,

T., Schedule-dependent inhibition of thymidylate synthase by 5-fluorouracil in gastric cancer,

Cancer, 70(12), 2761-5, 1992.

(69) Meta-analysis Group in Cancer, Efficacy of intravenous continuous infusion of

fluorouracil compared with bolus administration in advanced colorectal cancer, J Clin Oncol,

16(1), 301-8, 1998.

(70) Tralongo, P., Di Mari, A., Scibilia, G., Bosco, V., Giudice, A., Respini, D. and Failla,

G., Prolonged 5-fluorouracil infusion in patients with metastatic colon cancer pretreated with

bolus schedule of the same agent, Anticancer Res, 15(2), 635-8, 1995.

(71) Guglielmi, A., Aschele, C., Grossi, F., Tixi, L. and Sobrero, A., Alternating bolus and

continuous infusion 5-fluorouracil: a strategy to overcome resistance to this fluoropyrimidine

in advanced colorectal cancer patients, Cytotechnology, 19(3), 215-9, 1996.

(72) Lang, D.A., Matthews, D.R., Burnett, M. and Turner, R.C., Brief, irregular

oscillations of basal plasma insulin and glucose concentrations in diabetic man, Diabetes, 30,

435-9, 1981.

(73) Matthews, D.R., Lang, D.A., Burnett, M. and Turner, R.C., Control of pulsatile

insulin secretion in man, Diabetologia, 24, 231-7, 1983.

(74) Mazar, N.A., Pharmacokinetic and pharmacodynamic aspects of polypeptide delivery, J

Contr Rel, 11, 343, 1990.

(75) Vickey, B.H., Comparison of the potential for therapeutic utilities with gonadotropin-

releasing hormone agonists and antagonists, Endocrinol Rev, 7, 115-24, 1986.

(76) Breimer, D.D., Pharmacokinetic and pharmacodynamic basis for peptide drug delivery

system design, J Contr Rel, 21, 5-10, 1992.

(77) Handelsman, D.J., Cummins, J.T. and Clarke, I.J., Pharmacodynamics of

gonadotropin-releasing hormone. 1. Effects of gonadotropin-releasing hormone pulse contour

on pitutary luteinizing hormone secretion in vivo in sheep, Neuroendocrinology, 48, 432-8,

1988.

(78) Ward, G.M., The insulin receptor concept and its relation to the treatment of diabetes,

Drugs, 33, 156-70, 1987.

(79) Moore, J.G. and Halberg, F., Circadian rhythm of gastric acid secretion in men with

active duodenal ulcer, Dig Dis Sci, 31(11), 1185-91, 1986.

(80) Cederberg, C., Thomson, A.B., Mahachai, V., Westin, J.A., Kirdeikis, P., Fisher, D.,

Zuk, L. and Marriage, B., Effect of intravenous and oral omeprazole on 24-hour intragastric

60

acidity in duodenal ulcer patients, Gastroenterology, 103(3), 913-8, 1992.

(81) Howden, C.W., Burget, D.W. and Hunt, R.H., Appropriate acid suppression for

optimal healing of duodenal ulcer and gastro-oesophageal reflux disease, Scand J

Gastroenterol Suppl, 201, 79-82, 1994.

(82) Colin Jones, D.G., The role and limitations of H2-receptor antagonists in the treatment

of gastro-oesophageal reflux disease, Aliment Pharmacol Ther, 1, 9-14, 1995.

(83) Schentag, J.J. and Goss, T.F., Pharmacokinetics and pharmacodynamics of acid-

suppressive agents in patients with gastroesophageal reflux disease, Am J Hosp Pharm, 50(4

Suppl 1), S7-10, 1993.

(84) Netzer, P., Gaia, C., Sandoz, M., Huluk, T., Gut, A., Halter, F., Husler, J. and

Inauen, W., Effect of repeated injection and continuous infusion of omeprazole and

ranitidine on intragastric pH over 72 hours, Am J Gastroenterol, 94(2), 351-7, 1999.

(85) Labenz, J., Peitz, U., Leusing, C., Tillenburg, B., Blum, A.L. and Borsch, G.,

Efficacy of primed infusions with high dose ranitidine and omeprazole to maintain high

intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled

study, Gut, 40(1), 36-41, 1997.

(86) Hurlimann, S., Abbuhl, B., Inauen, W. and Halter, F., Comparison of acid inhibition

by either oral high-dose ranitidine or omeprazole, Aliment Pharmacol Ther, 8(2), 193-201,

1994.

(87) Scott, D.R., Besancon, M., Sachs, G. and Helander, H., Effects of antisecretory agents

on parietal cell structure and H/K-ATPase levels in rabbit gastric mucosa in vivo, Dig Dis Sci,

39(10), 2118-26, 1994.

(88) Frank, W., Karlstadt, R., Rockhold, F., Palmer, R., Malone, M. and Young, M.,

Comparison between continuous and intermittent infusion regimens of cimetidine in ulcer

patients [published erratum appears in Clin Pharmacol Ther 1989 Nov;46(5):500], Clin

Pharmacol Ther, 46(2), 234-9, 1989.

(89) Sanders, S.W., Buchi, K.N., Moore, J.G. and Bishop, A.L., Pharmacodynamics of

intravenous ranitidine after bolus and continuous infusion in patients with healed duodenal

ulcers, Clin Pharmacol Ther, 46(5), 545-51, 1989.

(90) Heiselman, D.E., Hulisz, D.T., Fricker, R., Bredle, D.L. and Black, L.D.,

Randomized comparison of gastric pH control with intermittent and continuous intravenous

infusion of famotidine in ICU patients, Am J Gastroenterol, 90(2), 277-9, 1995.

(91) Ballesteros, M.A., Hogan, D.L., Koss, M.A. and Isenberg, J.I., Bolus or intravenous

infusion of ranitidine: effects on gastric pH and acid secretion. A comparison of relative

efficacy and cost, Ann Intern Med, 112(5), 334-9, 1990.

(92) Savarino, V., Mela, G.S., Zentilin, P., Sumberaz, A., Cutela, P. and Celle, G., Single

61

morning and nightly doses of ranitidine 300 mg: an appraisal of their antisecretory effects by

continuous pH monitoring, Digestion, 48(3), 141-8, 1991.

(93) Patel, N., Ward, U., Rogers, M.J. and Primrose, J.N., Night-time or morning dosing

with H2-receptor antagonists: studies on acid inhibition in normal subjects, Aliment

Pharmacol Ther, 6(3), 381-7, 1992.

(94) Marenco, G., Menardo, G., Pallini, P., Rossini, F.P. and Saggioro, A., Comparison

between single morning and bedtime doses of 40 mg famotidine for the treatment of duodenal

ulcer, Aliment Pharmacol Ther, 3(3), 285-91, 1989.

(95) Okada, M., Yao, T., Sakurai, T., Arita, M., Okabe, N., Iida, M., Okada, Y. and

Koga, T., A comparative study of once-a-day morning and once-a-day bedtime

administration of 40 mg famotidine in treating gastric ulcers, Am J Gastroenterol, 87(8),

1009-13, 1992.

(96) Savarino, V., Mela, G.S., Zentilin, P., Cutela, P., Mansi, C., Vassallo, A., Franceschi,

M., Mela, M.R., Dallorto, E. and Celle, G., Antisecretory effect of three premeal doses of

cimetidine 400 mg versus a single morning dose of omeprazole 20 mg: pathophysiological

implications for duodenal ulcer treatment, Am J Gastroenterol, 88(7), 1088-92, 1993.

(97) Hartmann, M., Ehrlich, A., Fuder, H., Luhmann, R., Emeklibas, S., Timmer, W.,

Wurst, W. and Lucker, P.W., Equipotent inhibition of gastric acid secretion by equal doses

of oral or intravenous pantoprazole, Aliment Pharmacol Ther, 12(10), 1027-32, 1998.

(98) Kuo, B. and Castell, D.O., Optimal dosing of omeprazole 40 mg daily: effects on

gastric and esophageal pH and serum gastrin in healthy controls, Am J Gastroenterol, 91(8),

1532-8, 1996.

(99) Cederberg, C., Andersson, T. and Skanberg, I., Omeprazole: pharmacokinetics and

metabolism in man, Scand J Gastroenterol Suppl, 166, 33-40, 1989.

(100) Inoue, M. and Nakamura, M., Studies of various administration methods for

lansoprazole injection using 24-hour intragastric pH monitoring, J Clin Gastroenterol, 20(2),

S17-21, 1995.

(101) Aoki, T., Intravenous administration of lansoprazole: a preliminary study of dose

ranging and efficacy in upper gastrointestinal bleeding, Aliment Pharmacol Ther, 1(9 Suppl),

51-7, 1995.

(102) Bianchi Porro, G., Corinaldesi, R., Lazzaroni, M., Barbara, L., Capurso, L.,

Paoluzi, P., Mangiameli, A., Sabbatini, F., Franceschi, M. and Bolling, E., Long term

treatment with omeprazole 20 mg three days a week or 10 mg daily in the prevention of

duodenal ulcer relapse, Aliment Pharmacol Ther, 8(5), 541-8, 1994.

(103) Vigneri, S., Savarino, V., Mela, G.S., Termini, R., Di Mario, F., Pantalena, M.,

Zentilin, P., Muratore, F., Scialabba, A. and Badalamenti, S., A pharmacodynamic study

62

of two omeprazole regimens suitable for long-term treatment of duodenal ulcer, Scand J

Gastroenterol, 29(6), 488-92, 1994.

(104) Interdisciplinary Group for Ulcer Study, Six months of omeprazole 20 mg daily, 20

mg every other day or 40 mg at weekends in duodenal ulcer patients: a multicenter,

prospective, comparative study, Digestion, 56(3), 181-6, 1995.

(105) Chiverton, S.G., Howden, C.W., Burget, D.W. and Hunt, R.H., Omeprazole (20 mg)

daily given in the morning or evening: a comparison of effects on gastric acidity, and plasma

gastrin and omeprazole concentration, Aliment Pharmacol Ther, 6(1), 103-11, 1992.

(106) Sanders, S.W., Tolman, K.G., Greski, P.A., Jennings, D.E., Hoyos, P.A. and Page,

J.G., The effects of lansoprazole, a new H+,K(+)-ATPase inhibitor, on gastric pH and serum

gastrin, Aliment Pharmacol Ther, 6(3), 359-72, 1992.

(107) Sugiyama, M., Aoki, T. and Matsuo, Y., Determining the optimal dose of

lansoprazole injection by 24-hour intragastric pH monitoring, J Clin Gastroenterol, 20(2

Suppl), S14-6, 1995.

(108) Sanders, S.W., Pathogenesis and treatment of acid peptic disorders: comparison of

proton pump inhibitors with other antiulcer agents, Clin Ther, 18(1), 2-34; discussion 1, 1996.

(109) Russo, A. and Dattilo, M., Bedtime administration of lansoprazole does not modify its

greater efficacy vs ranitidine in the acute and long-term treatment of duodenal ulcer. Results

from a multicentre, randomised, double blind clinical trial, Ital J Gastroenterol Hepatol,

29(4), 312-9, 1997.

(110) World Health Organization, Cancer Pain Relief, Geneva, 1986.

(111) Ouellet, D.M.-C. and Pollack, G.M., Pharmacodynamics and tolerance development

during multiple intravenous bolus morphine administration in rats, J Pharmacol Exp Ther,

281(2), 713-20, 1997.

(112) Ling, G.S.F., Paul, D., Simantov, R. and Pasternak, G.W., Differential development

of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone

release in a morphine infusion model, Life Sci, 45, 1627-36, 1989.

(113) Kissin, I., Brown, P.T., Robinson, C.A. and Bradley, E.L., Acute tolerance in

morphine analgesia: Continuous infusion and single injection in rats, Anesthesiology, 74, 166-

71, 1991.

(114) Ouellet, D.M.-C. and Pollack, G.M., A pharmacokinetic-pharmacodynamic model of

tolerance to morphine analgesia during infusion to rats, J Pharmacokinet Biopharm, 23, 531-

49, 1995.

(115) Yamamoto, T., Ohno, M. and Ueki, S., A selective opioid agonist, U-50,488H, blocks

the development of tolerance to morphine analgesia in rats, Eur J Pharmacol, 156, 173-6,

1988.

63

(116) Trujillo, K.A. and Akil, H., Inhibition of morphine tolerance and dependence by the

NMDA receptor antagonist MK-801, Science, 251, 85-7, 1991.

(117) Ekblom, M., Hammarlund-Udenaes, M. and Paalzow, L., Modeling of tolerance

development and rebound effect during different intravenous administrations of morphine to

rats, J Pharm Exp Ther, 266, 244-52, 1993.

(118) Kaiko, R.F., Pharmacokinetics and pharmacodynamics of controlled-release opioids,

Acta Anesthesiol Scand, 41, 166-74, 1997.

(119) Smith, K.J., Miller, A.J., Sinclair, K.A. and et al., A novel once-daily morphine

preparation: pharmacokinetic development: Proceedings of the 8th World Congress of Pain.

International Association for the Study of Pain, Vancouver, 1996, pp 284-5.

(120) Gourlay, G.K., Cherry, D.A., Onley, M.M., Tordoff, S.G., Conn, D.A., Hood, G.M.

and Plummer, J.L., Pharmacokinetics and pharmacodynamics of twenty-four-hourly

Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain, Pain,

69, 295-302, 1997.

(121) Kaiko, R.F., Fitzmartin, R.D., Thomas, G.B. and Goldenheim, P.D., The

bioavailability of morphine in controlled-release 30-mg tablets per rectum compared with

immediate release 30-mg rectal suppositories and controlled-release 30-mg oral tablets,

Pharmacotherapy, 12, 107-13, 1992.

(122) Jacox, A., Carr, D.B. and Payne, R., New clinical-practice guidelines for the

management of pain in patients with cancer, New Engl J Med, 330, 651-5, 1993.

(123) Maddocks, I., Somogyi, A., Abbott, F., Hayball, P. and Parker, D., Attenuation of

morphine-induced delirium in palliative care by substitution with infusion of oxycodone, J

Pain Symptom Manag, 12, 182-9, 1996.

(124) Ross, F.B. and Smith, M.T., The intrinsic antinociceptive effects of oxycodone appear

to be kappa-opioid receptor mediated: Proceedings of the 8th World Congress on Pain,

Vancouver, British Columbia, Canada, 1996.

(125) Kaiko, R.F., Benziger, D., Cheng, C., Hou, Y. and Grandy, R., Analgesic onset and

potency of oral controlled release (CR) oxycodone and CR morphine, Clin Pharmacol Ther,

59, 130, 1996.

(126) Marshall, H.U.W., Porteous, C., McMillan, I., MacPherson, S.G. and Nimmo,

W.S., Relief of pain by infusion of morphine after operation: does tolerance develop? Br Med

J, 291, 19-21, 1985.

(127) Levy, G., Pharmacodynamic aspects of drug delivery, in Drug Delivery and its

Therapeutic Application, Prescott, L.F. and Nimmo, W.S., Eds, John Wiley, New York, 1991.

(128) Kaiko, R.F., Wallenstein, S.L., Rogers, A.G., Grabinski, P.Y. and Houde, R.W.,

Narcotics in the elderly, Med Clin North Am, 66, 1079-89, 1982.

64

(129) Levy, G., Correlation between drug concentrations and drug response in man -

pharmacokinetic considerations: Pharmacology and the Future of Man, Proc. 5th Congr.

Pharmacology. Karger, Basel, San Francisco, vol 34, 1973.

(130) Levy, G., Biopharmaceutical approaches to the development of proprietary drug

products: Proc A Res Sci Dev Conf, New York, vol 32, 1961.

(131) Walker, J.S., Pharmacokinetic-pharmacodynamic correlations of analgesics, in

Handbook of Pharmacokinetic / Pharmacodynamic Correlation, Derendorf, H. and

Hochhaus, G., Eds, CRC Press, 1995, pp 141-70.

(132) Shibasaki, J., Konishi, R., Kitasaki, T. and Koizumi, T., Relationship between blood

levels and analgesic effects of acetaminophen in mice, Chem Pharm Bull, 27, 129, 1979.

(133) Luthy, C.S., Collart, L. and Dayer, P., Administration profile controls acetaminophen

analgesia, Clin Pharm Ther, 53, 171, 1993.

(134) Nielsen, J.C., Bjerring, P., Arendt Nielsen, L. and Petterson, K.J., Analgesic

efficacy of immediate and sustained release paracetamol and plasma concentration of

paracetamol. Double blind, placebo-controlled evaluation using painful laser stimulation, Eur

J Clin Pharmacol, 42(3), 261-4, 1992.

(135) Sevelius, H., Runkel, R., Segre, E. and Bloomfield, S.S., Bioavailability of naproxen

sodium and its relationship to clinical analesic effects, Br J Clin Pharmacol, 30, 711, 1980.

(136) Monti, N.C., Gazzangia, A., Gianesello, V., Stroppolo, F. and Lodola, E., Activity

and pharmacokinetics of a new oral dosage form of soluble ibuprofen, Arzneim Forsch Drug

Res, 42, 556, 1992.

(137) Burns, J.W., Aitken, H.A., Bullingham, R.E., McArdle, C.S. and Kenny, G.N.,

Double-blind comparison of the morphine sparing effect of continuous and intermittent i.m.

administration of ketorolac, Br J Anaesth, 67(3), 235-8, 1991.

(138) Rehders, K., Simrock, R., Spahn, H., Mutschler, E. and Breddin, H.K., Plasma

salicylate levels and platelet function after acute and chronic administration of slow-release

acetylsalicylic acid, Eur J Clin Pharmacol, 27, 683, 1985.

(139) Martin, S.W., Stevens, A.J., Brennan, B.S., Rowland, M. and Houston, J.B.,

Pharmacodynamic comparison of regional drug delivery for non-steroidal anti-inflammatory

drugs, using the rat air-pouch model of inflammation, J Pharm Pharmacol, 47, 458-61, 1995.

(140) Fenner, H., Differntiating among nonsteroidal antiinflammatory drugs by

pharmacokinetic and pharmacodynamic profiles, Semin Arthritis Rheum, 26, 28-33, 1997.

(141) Labhasetwar, V. and Levy, R.J., Novel delivery of antiarrhythmic agents, Clin

Pharmacokinet, 29(1), 1-5, 1995.

(142) Labhasetwar, V., Underwood, T., Gallagher, M., Murphy, G., Langberg, J. and

Levy, R.J., Sotalol controlled-release systems for arrhythmias: in vitro characterization, in

65

vivo drug disposition, and electrophysiologic effects, J Pharm Sci, 83(2), 156-64, 1994.

(143) Breimer, D.D., The need for rate and time programming in future drug delivery:

pharmacokinetic, pharmacodynamic and clinical considerations, in Pulsatile Drug Delivery:

Current Applications and Future Trends, Gurny, R., Junginger, H.E. and Peppas, N.A., Eds,

Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, vol 33, 1987, pp 25-40.

(144) Kleinbloesem, C.H., van Brummelen, P., Danhof, M., Faber, H., Urquart, J. and

Breimer, D.D., Rate of increase in the plasma concentration of nifedipine is a major

determinant of its hemodynamic effects in humans, Clin Pharmacol Ther, 41, 26-30, 1987.

(145) Murdoch, D. and Brogden, R.N., Sustained release nifedipine formulations: an

appraisal of their current uses and prospective roles in the treatment of hypertension,

ischaemic heart disease and peripheral vascular disorders, Drugs, 41, 737-76, 1991.

(146) van Harten, J., van Brummelen, P., Zeegers, P.R.E.C.M., Danhof, M. and Breimer,

D.D., The influence of infusion rate on the pharmacokinetics and haemodynamic effects of

nisoldipine in man, Br J Clin Pharmacol, 25, 709-17, 1988.

(147) Abernethy, D.R., Problematic factors in pharmacodynamic studies, in

Pharmacokinetics and Pharmacodynamics: Current Problems and Potential Solutions,

Kroboth, P.D., Smith, R.B. and Juhl, R.P., Eds, Harvey Whitney, Cincinnati, vol 2, 1988, pp

60-74.

(148) Luscher, T.F. and Cosentino, F., The classification of calcium antagonists and their

selection in the treatment of hypertension. A reappraisal, Drugs, 55(4), 509-17, 1998.

(149) Defina, L.F., Bookstaver, D.A., Goldfinger, M.P. and Coffey, T.A., Nifedipine

gastointestinal therapeutic system versus nifedipine coat-core: comparison of efficacy via 24-

hour ambulatory blood pressure monitoring, Ann Pharmacother, 31, 819-22, 1997.

(150) Langtry, H.D. and Spencer, C.M., Nisoldipine coat-core. A review of its

pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of

ischaemic heart disease, Drugs, 53(5), 867-84, 1997.

(151) Muirhead, D.C., Norris, R.J., Cockayne, D. and Hill, G.W.R., Pharmacokinetics of

once-daily verapamil: Comparative bioavailability af two sustained-release formulations, Br J

Clin Pract, 42 (suppl 60), 14-9, 1988.

(152) McMahon, F.G. and Reder, R.F., The relationship of dose to the anti-hypertensive

response of verapamil-sustained release in patients wit hmild to moderate essential

hypertension, J Clin Pharmacol, 29, 1003-7, 1989.

(153) Dougall, H.T. and McLay, J., A comparative review of the adverse effects of calcium

antagonists, Drug Saf, 15(2), 91-106, 1996.

(154) van Zwieten, P. and Pfaffendorf, M., Pharmacology of the dihydropyridine calcium

antagonists: relationship between lipophilicity and pharmacodynamic responses, J Hypertens,

66

11 (Suppl. 6), S3-8, 1993.

(155) Alvan, G., Helleday, L., Lindholm, A., Sanz, E. and Villen, T., Diuretic effect and

diuretic efficiency after intravenous dosage of frusemide, Br J Clin Pharmacol, 29(2), 215-9,

1990.

(156) Wakelkamp, M., Alvan, G. and Paintaud, G., Natriuretic efficiency of frusemide as a

consequence of drug input rate, Br J Clin Pharmacol, 43(5), 481-91, 1997.

(157) Wakelkamp, M., Alvan, G., Gabrielsson, J. and Paintaud, G., Pharmacodynamic

modeling of furosemide tolerance after multiple intravenous administration, Clin Pharmacol

Ther, 60(1), 75-88, 1996.

(158) Alvan, G., Paintaud, G. and Wakelkamp, M., The efficiency concept in

pharmacodynamics, Clin Pharmacokinet, 36(5), 375-89, 1999.

(159) Franson, K.L., Kuk, J.M., Lam, N.P. and Lau, A.H., Gender effect on diuretic

response to hydrochlorothiazide and furosemide, Int J Clin Pharmacol Ther, 34(3), 101-5,

1996.

(160) Fujimura, A., Ohira, H., Shiga, T., Ohashi, K. and Ebihara, A.,

Chronopharmacology of furosemide in the elderly, J Clin Pharmacol, 32(9), 838-42, 1992.

(161) Wakelkamp, M., Alvan, G., Scheinin, H. and Gabrielsson, J., The influence of drug

input rate on the development of tolerance to frusemide, Br J Clin Pharmacol, 46(5), 479-87,

1998.

(162) Park, K.J., Yoon, W.H., Shin, W.G. and Lee, M.G., Effects of the rate and

composition of fluid replacement on the pharmacokinetics and pharmacodynamics of

intravenous azosemide, Biopharm Drug Dispos, 18(7), 595-610, 1997.

(163) Brater, D.C., Diuretic pharmacokinetics and pharmacodynamics, in The in vivo study

of drug action: Principles and applications of kinetic-dynamic modeling, van Boxtel, C.J.,

Holford, N.H.G. and Danhof, M., Eds, Elsevier Science, Amsterdam, 1992, pp 253-75.

(164) Ponto, L.L. and Schoenwald, R.D., Furosemide (frusemide). A pharmacokinetic /

pharmacodynamic review (Part II), Clin Pharmacokinet, 18(6), 460-71, 1990.

(165) Brater, D.C., Diuretic therapy, N Engl J Med, 339(6), 387-95, 1998.

(166) Vanky, F., Broquist, M. and Svedjeholm, R., Addition of a thiazide: an effective

remedy for furosemide resistance after cardiac operations, Ann Thorac Surg, 63(4), 993-7,

1997.

(167) Rudy, D.W., Gehr, T.W., Matzke, G.R., Kramer, W.G., Sica, D.A. and Brater,

D.C., The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal

insufficiency, Clin Pharmacol Ther, 56(1), 39-47, 1994.

(168) Brater, D.C., Diuretic resistance: mechanisms and therapeutic strategies, Cardiology,

2, 57-67, 1994.

67

(169) Eades, S.K. and Christensen, M.L., The clinical pharmacology of loop diuretics in the

pediatric patient, Pediatr Nephrol, 12(7), 603-16, 1998.

(170) Murray, M.D., Haag, K.M., Black, P.K., Hall, S.D. and Brater, D.C., Variable

furosemide absorption and poor predictability of response in elderly patients,

Pharmacotherapy, 17(1), 98-106, 1997.

(171) Ferguson, J.A., Sundblad, K.J., Becker, P.K., Gorski, J.C., Rudy, D.W. and

Brater, D.C., Role of duration of diuretic effect in preventing sodium retention, Clin

Pharmacol Ther, 62(2), 203-8, 1997.

(172) Park, K.J., Yoon, W.H., Shin, W.G. and Lee, M.G., The effect of intravenous

infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of

azosemide in rabbits, Biopharm Drug Dispos, 18(1), 41-52, 1997.

(173) Rudy, D.W., Voelker, J.R., Greene, P.K., Esparza, F.A. and Brater, D.C., Loop

diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus

therapy, Ann Intern Med, 115(5), 360-6, 1991.

(174) Martin, S.J. and Danziger, L.H., Continuous infusion of loop diuretics in the critically

ill: a review of the literature, Crit Care Med, 22(8), 1323-9, 1994.

(175) Beermann, B., Kinetics and dynamics of furosemide and slow-acting furosemide, Clin

Pharmacol Ther, 32(5), 584-91, 1982.

(176) Alvan, G., Paintaud, G., Eckernas, S.A. and Grahnen, A., Discrepancy between

bioavailability as estimated from urinary recovery of frusemide and total diuretic effect, Br J

Clin Pharmacol, 34(1), 47-52, 1992.

(177) Ritschel, W.A., Menon, A. and Sakr, A., Biopharmaceutic evaluation of furosemide

as a potential candidate for a modified release peroral dosage form, Methods Find Exp Clin

Pharmacol, 13(9), 629-36, 1991.

(178) Menon, A., Ritschel, W.A. and Sakr, A., Development and evaluation of a monolithic

floating dosage form for furosemide, J Pharm Sci, 83(2), 239-45, 1994.

(179) Akiyama, Y., Nagahara, N., Nara, E., Kitano, M., Iwasa, S., Yamamoto, I., Azuma,

J. and Ogawa, Y., Evaluation of oral mucoadhesive microspheres in man on the basis of the

pharmacokinetics of furosemide and riboflavin, compounds with limited gastrointestinal

absorption sites, J Pharm Pharmacol, 50(2), 159-66, 1998.

(180) Elsner, D., Muders, F., Muntze, A., Kromer, E.P., Forssmann, W.G. and Riegger,

G.A., Efficacy of prolonged infusion of urodilatin [ANP-(95-126)] in patients with congestive

heart failure, Am Heart J, 129(4), 766-73, 1995.

(181) Conte, G., Bellizzi, V., Cianciaruso, B., Minutolo, R., Fuiano, G. and De Nicola, L.,

Physiologic role and diuretic efficacy of atrial natriuretic peptide in health and chronic renal

disease, Kidney Int, 59(Suppl 32), S28-32, 1997.

68

(182) Lomnicky, Y., Friedman, M., Luria, M.H., Raz, I. and Hoffman, A., The effect of

the mode of administration on the hypolipidaemic activity of niacin: continuous

gastrointestinal administration of low-dose niacin improves lipid-lowering efficacy in

experimentally-induced hyperlipidaemic rats, J Pharm Pharmacol, 50(11), 1233-9, 1998.

(183) Brown, B.G., Bardsley, J., Poulin, D., Hillger, L.A., Dowdy, A., Maher, V.M.G.,

Zhao, X., Albers, J.J. and Knopp, R.H., Moderate dose, three-drug therapy with niacin,

lovastatin and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients

with hyperlipidemia and coronary artery disease, Am J Cardiol, 80, 111-5, 1997.

(184) Luria, M.H., Effect of low-dose niacin on high-density lipoprotein cholesterol and total

cholesterol/high-density lipoprotein cholesterol ratio, Arch Intern Med, 148, 2493-5, 1988.

(185) Goa, K.L., Barradell, L.B. and Plosker, G.L., Bezafibrate: An update of its

pharmacology and use in the management of dyslipidaemia, Drugs, 52, 725-53, 1996.

(186) Hoffman, A., Lomnicky, Y., Luria, M.H., Gilhar, D. and Friedman, M., Improved

lipid lowering activity of bezafibrate following continuous gastrointestinal administration:

Pharmacodynamic rationale for sustained release preparation of the drug, Pharm Res, 16(7),

1093-7, 1999.

(187) McClelland, G.A., Stibbs, R.J., Fix, J.A., Pogany, S.A. and Zentner, G.M.,

Enhancement of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor

efficacy through administration of a controlled-porosity osmotic pump dosage form, Pharm

Res, 8, 873-6, 1991.

(188) Contin, M., Riva, R., Martinelli, P., Cortelli, P., Albani, F. and Baruzzi, A.,

Longitudinal monitoring of the levodopa concentration-effect relationship in Parkinson's

disease, Neurology, 44, 1287-92, 1994.

(189) Contin, M., Riva, R., Martinelli, P., Albani, F. and Baruzzi, A., Effect of meal

timing on the kinetic-dynamic profile of levodopa/carbidopa controlled release in

parkinsonian patients, Eur J Clin Pharmacol, 54, 303-8, 1998.

(190) Harder, S., Baas, H., Bergemann, N., Demisch, L. and Rietbrock, S., Concentration-

effect relationship of levodopa in patients with Parkinson's disease after oral administration of

an immediate release and a controlled release formulation, Br J Clin Pharmacol, 39, 39-44,

1995.

(191) Capildeo, R., Implications of the 5-year CR FIRST trial, Neurology, 50 (Suppl. 6),

S15-7, 1998.

(192) Wolters, E.C. and Tesselaar, H.J., International (NL-UK) double-blind study of

Sinemet CR and standard Sinemet (25/100) in 170 patients with fluctuating Parkinson's

disease, J Neurol, 243(3), 235-40, 1996.

(193) Dupont, E., Andersen, A., Boas, J., Boisen, E., Borgmann, R., Helgetveit, A.C.,

69

Kjaer, M.O., Kristensen, T.N., Mikkelsen, B., Pakkenberg, H., Presthus, J., Stien, R.,

Worm Petersen, J. and Buch, D., Sustained-release Madopar HBS compared with standard

Madopar in the long-term treatment of de novo parkinsonian patients, Acta Neurol Scand,

93(1), 14-20, 1996.

(194) Bredberg, E., Nilsson, D., Johansson, K., Aquilonious, S.-M., Johnels, B., Nystrom,

C. and Paalzow, L., Intraduodenal infusion of a water-based levodopa dispersion for

optimization of the therapeutic effect in severe Parkinson's disease, Eur J Clin Pharmacol, 45,

117-22, 1993.

(195) Nilsson, D., Aquilonious, S.-M., Lundqvist, T., Nystrom, C. and Paalzow, L., Long

term pharmacokinetic and pharmacodynamic studies of intraduodenal levodopa infusion in

severe Parkinson's disease, Eur J Clin Pharmacol, , 1997.

(196) Woodworth, J.R., Howey, D.C. and Bowsher, R.R., Establishment of time-action

profiles for regular and NPH insulin using pharmacodynamic modeling, Diabetes Care, 17(1),

64-9, 1994.

(197) Hoffman, A. and Ziv, E., Pharmacokinetic considerations of new insulin formulations

and routes of administration, Clin Pharmacokinet, 33(4), 285-301, 1997.

(198) Marchetti, P., Scharp, D.W., McLear, M., Gingerich, R., Finke, E., Olack, B.,

Swanson, C., Giannarelli, R., Navalesi, R. and Lacy, P.E., Pulsatile insulin secretion from

isolated human pancreatic islets, Diabetes, 43(6), 827-30, 1994.

(199) Simon, C., Ultradian pulsatility of plasma glucose and insulin secretion rate: circadian

and sleep modulation, Horm Res, 49(3-4), 185-90, 1998.

(200) Paolisso, G., Scheen, A.J., Giugliano, D., Sgambato, S., Albert, A., Varricchio, M.,

D'Onofrio, F. and Lefebvre, P.J., Pulsatile insulin delivery has greater metabolic effects

than continuous hormone administration in man: importance of pulse frequency, J Clin

Endocrinol Metab, 72(3), 607-15, 1991.

(201) Paolisso, G., Sgambato, S., Varricchio, M., Scheen, A.J., D'Onofrio, F. and

Lefebvre, P., Insulin effects on glucose kinetics in non-insulin-dependent diabetic patients

with secondary failure to hypoglycaemic agents: role of different modes and rates of delivery,

Eur J Med, 1(5), 261-7, 1992.

(202) Bratusch Marrain, P.R., Komjati, M. and Waldhausl, W.K., Efficacy of pulsatile

versus continuous insulin administration on hepatic glucose production and glucose utilization

in type I diabetic humans, Diabetes, 35(8), 922-6, 1986.

(203) Heinemann, L., Sonnenberg, G.E., Hohmann, A., Ritzenhoff, A., Berger, M., Benn,

J., Sonksen, P., Kelley, D., Gerich, J., Aoki, T. and et al., Pulsatile insulin infusion and

glucose-homeostasis in well-controlled type 1 (insulin-dependent) diabetic patients, J Intern

Med, 226(5), 325-30, 1989.

70

(204) Kerner, W., Bruckel, J., Zier, H., Arias, P., Thun, C., Moncayo, R. and Pfeiffer,

E.F., Similar effects of pulsatile and constant intravenous insulin delivery, Diabetes Res Clin

Pract, 4(4), 269-74, 1988.

(205) Schmitz, O., Pedersen, S.B., Mengel, A., Porksen, N., Bak, J., Moller, N.,

Richelsen, B., Alberti, K.G., Butler, P.C. and Orskov, H., Augmented effect of short-term

pulsatile versus continuous insulin delivery on lipid metabolism but similar effect on whole-

body glucose metabolism in obese subjects, Metabolism, 43(7), 842-6, 1994.

(206) Logan Darrough, M., Pulsatile i.v. insulin therapy for severely out of control diabetes,

J Intraven Nurs, 18(3), 124-8, 1995.

(207) Nevalainen, P.I., Lahtela, J.T., Mustonen, J. and Pasternack, A., Subcutaneous and

intraperitoneal insulin therapy in diabetic patients on CAPD, Perit Dial Int, 16(1), S288-91,

1996.

(208) Tzamaloukas, A.H. and Oreopoulos, D.G., Subcutaneous versus intraperitoneal

insulin in the management of diabetics on CAPD: a review, Adv Perit Dial, 7, 81-5, 1991.

(209) Hinchcliffe, M. and Illum, L., Intranasal insulin delivery and therapy, Adv Drug

Delivery Rev, 35(2,3), 199-234, 1999.

(210) Patton, J.S., Bukar, J. and Nagarajan, S., Inhaled insulin, Adv Drug Delivery Rev,

35(2,3), 235-47, 1999.

(211) Carino, G.P. and Mathiowitz, E., Oral insulin delivery, Adv Drug Delivery Rev,

35(2,3), 249-57, 1999.

(212) Jennings, A.M., Lewis, K.S., Murdoch, S., Talbot, J.F., Bradley, C. and Ward,

J.D., Randomized trial comparing continuous subcutaneous insulin infusion and conventional

insulin therapy in type II diabetic patients poorly controlled with sulfonylureas, Diabetes

Care, 14(8), 738-44, 1991.

(213) Haakens, K., Hanssen, K.F., Dahl Jorgensen, K., Vaaler, S., Aagenaes, O. and

Mosand, R., Continuous subcutaneous insulin infusion (CSII), multiple injections (MI) and

conventional insulin therapy (CT) in self-selecting insulin-dependent diabetic patients. A

comparison of metabolic control, acute complications and patient preferences, J Intern Med,

228(5), 457-64, 1990.

(214) Butkiewicz, E.K., Leibson, C.L., O'Brien, P.C., Palumbo, P.J. and Rizza, R.A.,

Insulin therapy for diabetic ketoacidosis. Bolus insulin injection versus continuous insulin

infusion, Diabetes Care, 18(8), 1187-90, 1995.

(215) Wang, P.R. and Chien, Y.W., Day-night differences in the kinetics and dynamics of

insulin: diabetic versus normal Yucatan minipigs, Chronobiol Int, 13(3), 213-25, 1996.

(216) Trovati, M., Bruno, A., Lorenzati, R., Caselle, M.T., Pagani, A., Gorzegno, G. and

Pagano, G., Preprandial and postprandial variations of insulin sensitivity in different times of

71

the day assessed by the artificial pancreas in type I diabetics, Chronobiologia, 8(4), 333-40,

1981.

(217) Trumper, B.G., Reschke, K. and Molling, J., Circadian variation of insulin

requirement in insulin dependent diabetes mellitus. The relationship between circadian

change in insulin demand and diurnal patterns of growth hormone, cortisol and glucagon

during euglycemia, Horm Metab Res, 27(3), 141-7, 1995.

(218) Cusi, K., Cunningham, G.R. and Comstock, J.P., Safety and efficacy of normalizing

fasting glucose with bedtime NPH insulin alone in NIDDM, Diabetes Care, 18(6), 843-51,

1995.

(219) Kanc, K., Janssen, M.M., Keulen, E.T., Jacobs, M.A., Popp Snijders, C., Snoek,

F.J. and Heine, R.J., Substitution of night-time continuous subcutaneous insulin infusion

therapy for bedtime NPH insulin in a multiple injection regimen improves counterregulatory

hormonal responses and warning symptoms of hypoglycaemia in IDDM, Diabetologia, 41(3),

322-9, 1998.

(220) Jaremko, J. and Rorstad, O., Advances toward the implantable artificial pancreas for

treatment of diabetes, Diabetes Care, 21(3), 444-50, 1998.

(221) Smits, P. and Thien, T., Cardiovascular effects of sulphonylurea derivatives.

Implications for the treatment of NIDDM? Diabetologia, 38(1), 116-21, 1995.

(222) Schotborgh, C.E. and Wilde, A.A., Sulfonylurea derivatives in cardiovascular

research and in cardiovascular patients, Cardiovasc Res, 34(1), 73-80, 1997.

(223) Melander, A., Donnelly, R. and Rydberg, T., Is there a concentration-effect

relationship for sulphonylureas? Clin Pharmacokinet, 34(3), 181-8, 1998.

(224) Melander, A., Lebovitz, H.E. and Faber, O.K., Sulfonylureas. Why, which, and how?

Diabetes Care, 3, 18-25, 1990.

(225) Karam, J.H., Sanz, N., Salamon, E. and Nolte, M.S., Selective unresponsiveness of

pancreatic beta-cells to acute sulfonylurea stimulation during sulfonylurea therapy in

NIDDM, Diabetes, 35(12), 1314-20, 1986.

(226) Rydberg, T., Jonsson, A., Karlsson, M.O. and Melander, A., Concentration-effect

relations of glibenclamide and its active metabolites in man: modelling of pharmacokinetics

and pharmacodynamics, Br J Clin Pharmacol, 43(4), 373-81, 1997.

(227) Cusi, K. and DeFronzo, R.A., Metformin: a review of its metabolic effects, Diabet

Rev, 6(2), 89-131, 1998.

(228) Wiernsperger, N., Preclinical pharmacology of biguanides, in Oral antidiabetics,

Kuhlmann, J. and Puls, W., Eds, Springer-Verlag, Berlin, 1996, pp .

(229) Marchetti, P., Benzi, L., Cecchetti, P., Giannarelli, R., Boni, C., Ciociaro, D.,

Ciccarone, A.M., Di Cianni, G., Zappella, A. and Navalesi, R., Plasma biguanide levels are

72

correlated with metabolic effects in diabetic patients, Clin Pharmacol Ther, 41(4), 450-4,

1987.

(230) Marchetti, P., Gregorio, F., Benzi, L., Giannarelli, R., Cecchetti, P., Villani, G., Di

Cianni, G., Di Carlo, A., Brunetti, P. and Navalesi, R., Diurnal pattern of plasma

metformin concentrations and its relation to metabolic effects in type 2 (non-insulin-

dependent) diabetic patients, Diabete Metab, 16(6), 473-8, 1990.

(231) Stepensky, D., Srour, W., Friedman, M., Raz, I. and Hoffman, A., Dependency of

metformin hypoglycemic effect on mode of administration in diabetic rats: Measurement and

Kinetics of In Vivo Drug Effects. Advances in Simultaneous Pharmacokinetic /

Pharmacodynamic Modeling, Noordwijkerhout, The Netherlands, 1998.

(232) Vidon, N., Chaussade, S., Noel, M., Franchisseur, C., Huchet, B. and Bernier, J.J.,

Metformin in the digestive tract, Diabetes Res Clin Pract, 4, 223-9, 1988.

(233) Wilcock, C. and Bailey, C., Accumulation of metformin by tissues of the normal and

diabetic mouse, Xenobiotica, 24(1), 49-57, 1994.

(234) Abrams, J., A reapprisal of nitrate therapy, JAMA, 259, 396-401, 1988.

(235) Elkayam, U., Tolerance to organic nitrates: evidence, mechanisms, clinical relevance,

and strategies for prevention, Ann Intern Med, 114, 667-77, 1991.

(236) Fung, H.-L., Nitrate therapy: Is there an optimal substance and formulation? Eur Heart

J, 12 Suppl A, 9-12, 1991.

73