Seminar on… Dosage Regimen

Amruta S. SambarekarDept. Of Pharmaceutics

Maratha Mandal’s College of Pharmacy

Belgaum.

By

PART -II

Adjustment of Dosage in Renal

Impairment.

Adjustment of Dosage in Hepatic

Impairment.

Individualization.

Therapeutic Drug Monitoring.

Table of Contents

Adjustment of Dosage in Renal Impairment

In patient with renal failure, the half life of the drug is increase and its clearance drastically decreases if it is predominantly eliminated by way of excretion.

Hence, dosage adjustment should take into account the renal function of the patient and the fraction of unchanged drug excreted in urine. There are two additional method for dose adjustment in renal insuffiency if the Vd change is assumed to be negligible.

General Approach… No change in the desired or target

plasma concentration. Diminished renal clearance but

unchanged non-renal clearance. Unaltered drug protein binding &

volume of distribution in the renally impaired patient.

Unchanged drug absorption from the GIT.

Three Major Approaches are…

Dose adjustment based on Total body

clearance.

Dose adjustment based on Elimination

rate constant or Half life.

Dose adjustment in renal failure.

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Dose adjustment based on Total body clearance

The average drug conc. at steady-state css,av is a function of maintenance dose X0 , the fraction of dose absorbed F, the dosing interval ז & clearance Cl T of the drug.

F X0

X X

To be kept Assumed Decreased Needs

Constant Constant due to Disease adjustment

Css,av

Css,av F1

Cl

T

Xזז0

( )Cl T ז

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If ClT' , X0

represents the values for the renal ' ז & 'failure patient, then the eq. for dose adjustment is given as…

Rearranging in terms of dose & dose interval to be adjusted, the eq. is…

From the above eq., the regimen can be adjusted by

reduction in dosage or increase in dosing interval or a combination of both.

Css,av

X0

ClT זX0 '

ClT' ז '

X0 '

' ז

ClT' X0

ClT ז

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Dose adjustment based on Elimination rate constant or Half

life The average drug conc. at steady-state

css,av is a function of maintenance dose X0 , the fraction of dose absorbed F, the dosing interval ז & volume of distribution vd & t1/2 of the drug.

Where, the coefficient 1.44 is the reciprocal of 0.693.

Css,av 1.44 F X0 t1/2

Vdז

Css,av1.44 F

Vd

X t1/2 XX0

ז

To be kept normal

Assumed constant

increased due to disease

Needs adjustment

If t1/2 ' , X0 ' & ז ' represents the values for the renal failure patient, then the eq. for dose adjustment is given as…

Css,av t1/2 X0

זt1/2 ' X0

' ' ז

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Rearranging in terms of dose & dose interval to be adjusted, the eq. is…

Because of prolongation of half life of a drug due to reduction in renal function, the time taken to achieve the desired plateau takes longer if the more severe is dysfunction, hence such patient sometimes need loading dose.

X0 '

' ז

t1/2 X0

t1/2 ' ז

Diseases are the major source of variation in drug response. Both pharmacokinetic and Pharmacodynamic of many drugs are altered by disease other than the one which is being treated.

Disease state :

Renal dysfunction

Uremia

Uremia :It is characterized by impaired Glomerular filtration and accumulation of fluid and protein metabolism.

In both the cases the half life of the drug are increased as a consequences drug accumulation and toxicity increases.

Renal dysfunction :It greatly impair the elimination of drug especially those that are primarily excreted by the kidney.Causes of renal failure are hypertension, diabetes mellitus

The influence of Hepatic disorder on the drug bioavailability & disposition is unpredictable because of the multiple effects that liver produces.

The altered response to drugs in liver disease could be due to decreased metabolizing capacity of the hepatocytes, impaired biliary elimination, due to biliary obstruction (e.g. Rifampicin accumulates in obstruction jaundice)

Adjustment of Dosage in Hepatic Impairment.

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Impaired Hepatic blood flow leading to an increase in bioavailability caused by a reduction in first pass metabolism (e.g Bioavailabilities of Morphine and Labetalol have been reported to double in patients with Cirrhosis)

Decreased protein binding and increased toxicity of drugs highly bound to plasma protein (e.g. Phenytoin, Warfarin) due to impaired albumin production, altered volume of distribution of drugs due to increased extracellular fluid.

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Oedema in liver disease may be increased by drugs that cause fluid retention (e.g. Acetylsalicylic acid, Ibuprofen, Prednisolone, Dexamethasone).

Generally, drug doses should be reduced in patients with hepatic dysfunction since clearance is reduced & bioavailability is increased in such a situation.

Glomerular filtration rate can be determined by following two methods :

Insulin clearance

Creatinine clearance

Renal function determination

For children (1-20 years) : Clcr =0.48 H X [W] 0.7

Scr [70]

For Adult (above 20 years) :

Males, Clcr = (140 – age) W 72 x Scr

Females, Clcr =(140 – age) W 85 x Scr

A direct method for determining creatinine clearance is :

Clcr = Rate of creatinine excretion Serum creatinine in mg %

Renal function. RF is calculated by following equation : RF= Clcr of patient Clcr of a normal person

Dose required by the patient with renal impairment : Normal dose X RF

Dosing interval : Normal interval/RF

Dose adjustment in renal failure when drug is eliminated both by renal and non renal mechanism : Normal dose = RF X [ fraction excreted X fraction eliminated] in urine non

renally

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Conclusion Ideally in planning ‘Dosage regimen’ drug

dosage adjustment is important in all critically ill patients with organ failures.

In treating such critically ill patients, drug treatment should be so carefully done in order to achieve steady state plasma concentration required within a known and safe effective therapeutic range.

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Individualization of Therapy

Same dose of drug may produce large differences in pharmacologic response in different individuals, this is called as intersubject variability.

For the rational drug therapy, requires individualization of dosage regimen.

To achieve optimum dosage regimen.

Sources of Variability

1) Pharmacokinetic Variability : Due to differences in drug conc. at the site

of action. Major causes are genetics, disease, age,

body wt. & drug-drug interactions.2) Pharmacodynamic Variability : Due to differences in effect produce by a given drug conc.

For individualization of drug therapy, a drug must be available in dosage forms of different dose strengths.

Depends on two major factors… i) Therapeutic Index & ii) The degree of intersubject variability. Hence, smaller the therapeutic index &

greater the variability, more the no. of dose strengths required.

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Steps involved in Individualization of Dosage regimen

Estimation of pharmacokinetic parameters in individual patient & determining their deviation from the population values to evaluate the extent of variability.

Attributing the variability to some measurable characteristics such as hepatic or renal disease, age, wt. etc.

Designing the new dosage regimen from collected data.

Dosing of Drug in Obese Patient :

IBW (men)=50Kg + 1Kg/2.5 cm above or below150 cm

in height

IBW (women)=45Kg +1Kg/2.5 cm above or below 150cm in height

Any person whose body weight is more than 25% above the IBW is considered as obese.

Dosing of drug in Neonates, Infants & Children

Mosteller’s equation:SA (in m2)=( height X weight )1/2

60Child’s maintenance dose can be calculated

from adult dose by using the following equation :

Child’s dose= SA of Child in m2 X Adult Dose

1.73 SA (in m2) = Body weight (Kg)0.7

The following relationship can also be written for child’s dose :

Child’s dose= [weight of child in Kg] 0.7 X Adult dose 70Dosing of drug in elderly :

A general equation that allows calculation of maintenance dose of any age except neonates & infants:

Patient’s dose=(weight in Kg)0.7(140- age in years)XAdult Dose

1660

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Therapeutic Drug Monitoring

Management of drug therapy in individual patient often requires evaluation of the response of the patients to the recommended dosage regimen, known as Therapeutic drug monitoring.

Depending on the drug & the disease to be treated, for management of drug therapy in individual patient, we need…

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I. Monitoring Therapeutic effect : E.g. prevention of an anticipated

attack of angina or shortening of duration of pain when attack occurs, through the use of Glyceryl trinitrate.

II. Monitoring Pharmacologic actions : E. g. Blood glucose lowering with

Insulin.III. Monitoring plasma drug conc. : E.g. Digoxin, Phenytoin etc.

Conclusion

Successful application of this monitoring therapy requires complete knowledge of pharmacokinetic parameter of the drug, the situation in which this parameters are likely to be altered & the extent to which they could be altered, & a sensitive, specific & accurate analytical method for determination of drug concentration.

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References

‘Biopharmaceutics & Pharmacokinetics’, A Treatise, D. M. Brahmankar & Sunil B. Jaiswal, Vallabh Prakashan, Pitampura, Delhi.

‘www.google.com

‘Text Book Of Biopharmaceutics & Pharmacokinetics”, Dr. Shobha Rani R. Hiremath.

Thank You !