1. Prof. Dr. Henny Lucida, Apt
Drug Dosage Regimen
Prof. Dr. Henny Lucida, Apt

2. Goals Optimum therapeutic response with minimum adverse effects
Individualization of drug dosage regimen, esp drugs with a narrow therapeutic window

3. 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
mEq/L
10-20 mcg/mL
4-10 mcg/mL
mcg/mL
20-40 mcg/mL

4. 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)

5. 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)

6. 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

7. 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

8. (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.

9. 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.

10. Empirical dosage regimens
Not based on pharmacokinetic variables, but on empirical clinical data, personal experience and clinical observations.

11. Constant-rate Regimens

12. Multiple-dose Regimens

13. Accumulation Index

14. 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)

15. 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

16. 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)

17. 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)

18. Design of dosage regimens from plasma conc

19. Design of dosage regimens from plasma conc

20. Maintenance of a peak conc

27. Case Study 1

28. Case Study 2

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

30. Case Study 4

31. Case Study 5

32. 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

33. 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.

34. 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

35. 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