clinical pharmacokinetics-ii [dosing of drugs, tdm]

DR. BADAR UDDINUMAR

To discuss dosing schedules of drugs

based on pharmacokinetic principles

To discuss therapeutic drug

monitoring

Effective dose: It is the amount of

drug which will produce specific

intensity of effect i.e.; either to treat

the disease or prevent the disease

successfully

Median effective dose (ED50): It is the amount of a drug which produces the desired therapeutic effect in 50% of experimental animals

OR It is the dose of a drug required to produce

a specific intensity of effect in 50% of individuals

It is measure of effectiveness of a drug

Lethal dose: It is the amount of a drug

which will kill certain percentage of

experimental animals to whom the drug is

administered

Fatal dose: When lethal dose reaches

100% or LD100 is known as fatal dose

Median lethal dose (LD50): It is the

amount of a drug which is fatal to 50%

of the experimental animals [i.e.; which kills 50% of the experimental

animals]

It is the measure of acute toxicity of

drugs

Initial loading dose: In some

conditions certain drugs are given in

large doses in the beginning to

obtain an effective blood level

rapidly, this is known as initial

loading dose

Maintenance dose: After achieving

a desired blood level by initial loading

dose, smaller quantity of drug is then

required to maintain the blood level,

this is known as maintenance dose

e.g. initial loading dose of sparfloxacin

is 400 mg. on the first day then

maintenance dose is 200 mg / day as

single daily dose Initial loading dose of digoxin is 1-1.5

mg the maintained at 0.25 mg once or

twice daily dose

Loading Dose

Dose = Cp(Target) x VdDose = Cp(Target) x Vd

What is the loading dose required for drug A if;

Target concentration is 10 mg/L Vd is 0.75 L/kg Patients weight is 75 kg

Answer is on the next slide

Dose = Target Concentration x VD

Vd = 0.75 L/kg x 75 kg = 56.25 L

Target Conc. = 10 mg/L Dose = 10 mg/L x 56.25 L = 565 mg This would probably be rounded to 560 or

even 500 mg

Maintenance Dose = CL x CpSSav

CpSSav is the target average steady state drug concentration

The units of CL are in L/hr or L/hr/kg

Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24

What maintenance dose is required for drug A if;

Target average SS concentration is 10 mg/L

CL of drug A is 0.015 L/kg/hr

Patient weighs 75 kg

Answer on next slide

Maintenance Dose = CL x CpSSav

CL = 0.015 L/hr/kg x 75 = 1.125 L/hr

Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr

So will need 11.25 x 24 mg per day = 270 mg

Effective Dose50 [ED50]

Toxic Dose50 [TD50]

Therapeutic Index

Therapeutic window

Not all people respond to a similar dose

of a drug in the exact same manner

This variability is based upon individual

differences and is associated with toxicity

DrugTherapeutic Concentration Range

Aminoglycoside (gentamicin, tobramycin)

0.5 < - > 8 mg/L

Digoxin 0.5 < - > 8 2.0 ug/L

Phenytoin 10 < - > 8 20 mg/L

Theophylline 10 < - > 8 20 mg/L

This variability is thought to be caused by:

•Pharmacokinetic factors contribute to differing concentrations of the drug at the target area

•Pharmacodynamic factors contribute to differing physiological responses to the same drug concentration -

•Unusual, idiosyncratic, genetically determined or allergic, immunologically sensitized responses

The therapeutic index (also known as therapeutic ratio), is a comparison (ratio) of the amount of a drug that causes the therapeutic effect to the amount that causes death

Quantitatively, it is the ratio of median lethal dose to median effective dose

It is an approximate assessment of the safety of the drugs

A high therapeutic

index is preferable

to a low one

This corresponds to a

situation in which one

would have to take a

much higher dose of a

drug to reach the

lethal threshold than

the dose taken to elicit

the therapeutic effect

Larger the TI greater is the relative safety of the drug

For therapeutic use TI of a drug must be more than one

A drug might have different TI depending on its clinical use e.g.; Aspirin used in headache TI is high

Aspirin used in Rheumatoid arthritis TI is very low

Drugs with high

TI:

Penicillin [dose up to

48 lac units]

Diazepam [up to

200 mg at once, LD

is 750 mg]

Drugs with low

TI:

Digitalis [digoxin]

Anticancer drugs

Phenobarbitone

Warfarin

In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50

The precision, possible in animal experiments may make it useful to estimate the potential benefit of a drug in humans

The therapeutic index of a drug in humans is almost never known with real precision

Drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses

The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated

For example, the dose range that provides relief from an ordinary headache in the great majority of patients should be very much lower than the dose range that produces serious toxicity

However, for treatment of a lethal disease such as Hodgkin's lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller

It is the ratio of the lethal dose to

1% of population to the effective

dose to 99% of the population

(LD1/ED99)

This is a better safety index than the LD50

for drugs that have both desirable and

undesirable effects, because it factors in

the ends of the spectrum where doses

may be necessary to produce a response

in one person but can, at the same dose,

be lethal in another

Useful range of concentration over

which a drug is therapeutically

beneficial

Therapeutic window may vary from

patient to patient

Drugs with narrow therapeutic windows

require smaller and more frequent doses

or a different method of administration

Drugs with slow elimination rates may

rapidly accumulate to toxic levels….can

choose to give one large initial dose,

following only with small doses

Some Principles

An established relationship between

concentration and response or toxicity

A sensitive and specific assay

An assay that is relatively easy to perform

A narrow therapeutic range

A need to enhance response/prevent

toxicity

Lack of therapeutic response

Toxic effects evident

Potential for non-compliance

Variability in relationship of dose and

concentration

Therapeutic/toxic actions not easily

quantified by clinical endpoints

Assuming patient is at steady-state Assuming patient is actually taking the drug

as prescribed Assuming patient is receiving drug as

prescribed Not knowing when the [drug] was measured in

relation to dose administration Assuming the patient is static and that changes

in condition don’t affect clearance

Not considering drug interactions

Invasive: blood, spinal fluid, biopsy Noninvasive: urine, feces, breath,

saliva

Most analytical methods designed for plasma analysis

C-14, H-3

At the end of the lecture the students will be able to-

Explain with examples the principles of dosing schedules of drugs based on pharmacokinetic principles

Explain with examples the clinical significance of therapeutic drug monitoring