ERLI SUSANTI07 131 062

Fakultas FarmasiUniversitas Andalas

CLINICAL PHARMACOKINETICS

Drug Dosage Regimen

Henny Lucida, PhD, Apt

Goals

• Optimum therapeutic response with minimum adverse effects

• Individualization of drug dosage regimen, esp drugs with a narrow therapeutic window

Drugs w/ narrow ther window

Drug Disease/condition Therapeutic window

Amikacin

Carbamazepine

Digoxin

Gentamicin

Lidocaine

Lithium

Phenytoin

Procainamide

Theophylline

Tobramycin

Valproic acid

Vancomycin

Gram-negative infection

Epilepsy

Cardiac dysfunction

Gram-negative infection

Ventricular arrhythmias

Manic & recurrent depression

Epilepsy

Ventricular arrhythmias

Asthma

Gram-negative infection

Epilepsy

Penicillin-resistant infection

20-30 mcg/mL

4-12 mcg/mL

1-2 ng/mL

5-10 mcg/mL

1-5 mcg/mL

0.6-1.2 mEq/L

10-20 mcg/mL

4-10 mcg/mL

10-20 mcg/mL

5-10 mcg/mL

50-100 mcg/mL

20-40 mcg/mL

Dosage regimen design

Dosage Regimen

Activity-toxicity-Therapeutic window-Side effects-Toxicity-conc-response rel

Pharmacokinetics:

ADME

Clinical Factors

-Patients (age, weight, patophysiologic cond

-Management of ther (multiple drug ther, convenience of regimen, compliance of patient)

Other factors:-Route of adm-Dosage form-Tolerance-dependence-Drug interaction-Cost

Dosage regimen design

• The most accurate approach to dosage regimen design is to calculate the dose based on the pharmacokinetics of the drug in the individual patient (not for initial dose; only for readjustment of the dose). The initial dose was estimated using average population pharmacokinetic parameters obtained from literature. Clin pharm softwares for drugs with narrow ther window are available (Datakinetics etc)

3 methods

1. Dosage regimens based on population averages:

(a) the fixed model

(b) the adaptive model

2. Dosage regimens based on partial pharmacokinetic parameters

3. Empirical dosage regimens

Dosage regimens based on population averages

• Obtained from clinical studies published in the drug literature (a) the fixed model, assumes that population average pharmacokinetic parameters may be used directly to calculate a dosage regimen for the patient without any alteration. Parameters such as : ka, F, VD apparent, and ke are assumed to remain constant; follow a one-compartment model. The practitioner may use the usual dosage suggested by the literature and/or make small adjustment based on the patient’s weight and/or age

(b) the adaptive model

dosage regimen was calculated by using patient variables such as: weight, age, sex, body surface area, and known patient patophysiology such as renal disease as well as the known population average pharmacokinetic parameters of the drug. This model assumes that drug clearance do not change from one dose to the next.

Dosage regimens based on partial pharmacokinetic parameters

• For drugs with unknown or unavailable pharmacokinetic profile, the pharmacokineticist needs to make some assumptions to calculate the dosage regimen. Exp: to let F equal 1 or 100%.

the risk of undermedicated or overmedicated. Assumptions will depend on the safety, efficacy and therapeutic range of the drug.

Empirical dosage regimens

• Not based on pharmacokinetic variables, but on empirical clinical data, personal experience and clinical observations.

Conversion from intravenous infusion to oral dosing

• In-patient out-patient

• Method: assumes that Css after IV infusion is identical to the desired C∞

av after multiple oral doses. Equation: