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2 Design of DOSAGE DESIGN

The document discusses factors to consider when designing drug dosage regimens, including route of administration, dose, dosage interval, and complications. It describes several methods for designing regimens, such as individualized dosing based on a patient's pharmacokinetics, population-based approaches, and using partial pharmacokinetic parameters or empirical methods when full information is unavailable. Nomograms are also discussed as a tool to simplify regimen calculations based on patient characteristics.

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Marjo
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405 views16 pages

2 Design of DOSAGE DESIGN

The document discusses factors to consider when designing drug dosage regimens, including route of administration, dose, dosage interval, and complications. It describes several methods for designing regimens, such as individualized dosing based on a patient's pharmacokinetics, population-based approaches, and using partial pharmacokinetic parameters or empirical methods when full information is unavailable. Nomograms are also discussed as a tool to simplify regimen calculations based on patient characteristics.

Uploaded by

Marjo
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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DESIGN OF DOSAGE REGIMEN

 Dosage regimen design is the selection of drug dosage, route,


and frequency of administration in an informed manner to
achieve therapeutic objectives

 Deliberate planning of drug therapy is necessary because the


administration of drugs usually involves risk of untoward effects

 Specific drugs have inherently different risks associated with


their use and a dosage regimen should be selected which will
maximize safety

 At the same time, the variability among patients in


pharmacodynamic response demands individualized dosing to
assure maximum efficacy
Factors to consider in Design of Drug Dosage Regimens
I. Route of Administration:
1. Drug absorption characteristics

2. Presence of presystemic elimination

3. Accumulation of drug at absorption site, e.g. intramuscular


depots

4. Need for immediate onset of action

5. Ease of administration

6. Half-life: infusion may be necessary for drugs with short t1/2


or sustained release formulation

7. Patient acceptance of route and dosage form


Factors to consider in Design of Drug Dosage Regimens…
II. Dose:
1. Therapeutic index: if high, consider benefits of loading dose

2.Volume of distribution: to estimate peak plasma


concentration

3. Documented nonlinearity of pharmacokinetics

4. Cost of medication

5. Half-life: tapering of dose may not be necessary for some


drugs with long t1/2
6. Availability of treatment for overdose

7. Existence of a therapeutic or toxic concentration range


Factors to consider in Design of Drug Dosage Regimens…
III. Dosage interval:
1. Half-life: dosage interval can generally be extended in
relation to half-life

2. Therapeutic index: the higher the TI, the longer an interval


can be spaced with higher doses

3. Body clearance: to evaluate accumulation

4. Side effects which may require special administration times,


e.g. bedtime to avoid sedation
Factors to consider in Design of Drug Dosage Regimens…
IV. Complications:
1. Analytical methodology and reliability in monitoring Cp

2. Active metabolites

3. Changing pathophysiology

4. Drug interactions

5. Auto or exogenous enzyme induction

6. Development of pharmacodynamic tolerance

7. Side effects not dose or concentration related

8. Need for baseline con. data with recent history of drug use
 Several methods may be used to design a dosage regimen
 Individualized dosage regimen

 Dosage regimen based on population average

 Dosage regimen based on partial pharmacokinetic


parameters

 Empirical dosage regimen


Individualized Dosage Regimen:
 Most accurate approach
 Dose calculated based on the pharmacokinetics of the drug in
the individual patient derived from measurement of serum /
plasma drug levels
 Not feasible for calculation of the initial dose, however,
readjustment of the dose is quite possible
 Most dosing program record the patient’s age and weight and
calculate the individual dose based on creatinine clearance and
lean body mass

Dosage Regimens based on Population Averages:


 Dosage regimen is calculated based on average
pharmacokinetic parameters obtained from clinical studies
published in the drug literature
Dosage Regimens based on Population Averages…
 There are two approaches followed
 Fixed model
 Adaptive model

Fixed Model:
 Assumes that population average pharmacokinetic parameters
may be used directly to calculate a dosage regimen for the
patient, without any alteration

 The practitioner may use the usual dosage suggested by the


literature and then make a small adjustment of the dosage based
on the patient’s weight and / or age
Fixed Model…
 Usually, pharmacokinetic parameters such as Ka, F, Vd, k are
assumed remain constant and most often drug is assumed to
follow one compartment open model

 When a multiple dose regimen is designed, multiple dosage


equations based on the principle of superposition are used to
evaluate the dose

Adaptive Model:
 This approach attempts to adapt or modify dosage regimen
according to the need of the patient

 Uses patient variable such as weight, age, sex, body surface


area, and known patient’s pathophysiology such as, renal
disease, as well as known population average pharmacokinetic
parameters of the drug
Adaptive model…
 This model generally assumes that pharmacokinetic parameters
such as drug clearance do not change from one dose to the next

 However, some adaptive models allow for continuously adaptive


change with time in order to simulate more closely the changing
process of drug disposition in the patient, especially during a
disease state

Dosage Regimen based on Partial Pharmacokinetic Parameters:


 For many drugs, the entire pharmacokinetic profile for the drug is
unknown or unavailable

 Therefore, the pharmacokineticist needs to make some


assumptions in order to calculate the dosage regimen

 These assumptions will depend on the safety, efficacy, and


therapeutic range of the drug
Dosage Regimen based on Partial Pharmacokinetic Parameters…
 The use of population pharmacokinetics uses average patient
population characteristics and only a few serum / plasma
concentration from the patient

 Population pharmacokinetic approaches to therapeutic drug


monitoring have increased with the increased availability of
computerized data bases and development of statistical tools for
the analysis of observational data

Empirical Dosage Regimens:


 In many cases, physician selects a dosage regimen of the
patient without using any pharmacokinetic variables

 The physician makes the decision based on empirical clinical


data, personal experience and clinical observations
A nomogram typically has three scales: two scales represent
known values and one scale is the scale where the result is read
off

 The known scales are placed on the outside; i.e. the result scale
is in the center

 Each known value of the calculation is marked on the outer


scales and a line is drawn between each mark

 Where the line and the inside scale intersects is the result

 Examples include, height – BMI – weight, total clearance –


maintenance dose – lean body weight, etc.
 For ease of calculation of dosage regimens, many clinicians rely
on nomograms to calculate the proper dosage regimen for their
patients

 The use of nomogram may give a quick dosage regimen


adjustment for patients with characteristics requiring adjustments
such as age, body weight, and physiologic state

 In general, nomogram of a drug is based on population


pharmacokinetic data collected and analyzed using a specific
pharmacokinetic model
 In order to keep the dosage regimen calculation simple,
complicated equations are often solved and their results
displayed diagrammatically on special scaled axes to produce a
simple dose recommendation based on patient information

 Some nomograms make use of certain physiologic parameters,


such as serum creatinine concentration, to help modify the
dosage regimen according to renal function

 For many marketed drugs, the manufacturer provides tabulated


general guidelines for use in establishing a dosage regimen for
patients, including loading and maintenance doses
 Examples of drugs for which nomograms are being used for
designing dosage regimen:
 Digoxin
 Warfarin
 Heparin
 Vancomycin
 Tacrolimus
 Phenytoin
 Clozapine

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