Prof. Dr. Henny Lucida, Apt Drug Dosage Regimen Prof. Dr. Henny Lucida, 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 Disease/condition Therapeutic window Amikacin Carbamazepine Digoxin Gentamicin Lidocaine Lithium Phenytoin Procainamide Theophylline Tobramycin Valproic acid Vancomycin Gram-negative infection Epilepsy Cardiac dysfunction Ventricular arrhythmias Manic & recurrent depression Asthma 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 50-100 mcg/mL 20-40 mcg/mL

Dosage regimen design Activity-toxicity -Therapeutic window -Side effects -Toxicity -conc-response rel Pharmacokinetics: ADME Dosage Regimen Other factors: -Route of adm -Dosage form -Tolerance-dependence -Drug interaction -Cost Clinical Factors -Patients (age, weight, patophysiologic cond -Management of ther (multiple drug ther, convenience of regimen, compliance of patient)

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.

Constant-rate Regimens

Multiple-dose Regimens

Accumulation Index

Dosage regimens for continuous maintenance of therapeutic conc Half-lives < 30 minutes low TI drugs : must be infused ex: heparin high TI : may be given less frequently (than t1/2) but with higher MD ex: Penicillin, 4 – 6 hr interval (t1/2 = 30 min)

Dosage regimens for continuous maintenance of therapeutic conc 30 min < t1/2 < 8 hr - low TI drugs: must be given every half- life or more frequently or by infusion ex: lidocain (90min) infusion, theophylline (3-6 doses/day) - high TI drugs: once every 1 – 3 t1/2 ex: cephalosporins (30min-3hr) 3 – 6 halflives

Dosage regimens for continuous maintenance of therapeutic conc 8 < t1/2 < 24 hr - the most convenience - a dose is given every half life, LD must be twice MD to achieve Css immediately ex: sulfamethoxazole (high TI) and clonidine (low TI)

Dosage regimens for continuous maintenance of therapeutic conc T1/2 > 24 hr administration once daily is convenient and promotes patient compliance Ex: Chloroquine (high TI), Digitoxin (low TI)

Design of dosage regimens from plasma conc

Design of dosage regimens from plasma conc

Maintenance of a peak conc

Case Study 1

Case Study 2

Case Study 3 the cumulation factor (CF): CF = 1 / 1 − e−kt

Case Study 4

Case Study 5

Study case 6 An antibiotic drug is to be given to an adult male patient (75 kg, 58 years old) by IV infusion. The drug is supplied in sterile vials containing 30 mL of the antibiotic solution at a concentration of 125 mg/mL. What rate (mL/min) would you infuse this patient to obtain a Css of 20 mg/mL? What loading dose would you suggest? Assume: one-compartment model, Vd = 0.5L/kg and t1/2 elimination = 3 hours

Study case 7 For prolonged surgical procedures, succinylcholine chloride is given by iv infusion for sustained muscle relaxation.A typical initial dose is 20 mg followed by continuous infusion of 4 mg/min. The infusion must be individualized because of variation in the kinetics of metabolism of succinylcholine. Estimate the elimination half-lives of succinylcholine in patients requiring 0.4 mg/min and 4 mg/min, respectively, to maintain 20 mg in the body.

Study case 8 . A patient with renal dysfunction received a dose of vancomycin. Cp were 22 and 15 mg/L at 24 and 48 hours after infusion respectively. Determine when the concentration would reach 10 mg/L! a. 54 hours b. 72 hours c. 96 hours d. 128 hours

Study case 9 Mr. J, a non smoking 60 kg patient with chronic obstructive pulmonary disease, is to be started on an oral regimen of aminophylline (85% of which is theophylline). The pharmacokinetic s parameter values for a typical patient population with this disease are: F = 1 (for theophylline), V=0.5 L/kg and CL= 40 mL/hr/kg. Design an oral dosage regimen of aminophylline (100 and 200 mg tablets are marketed) for this patient to attain and maintain a plasma conc within ther window 10 – 20 mg/L. The absorption of theophylline is complete and rapid