DETECTION OF CARBAMAZEPINE-INDUCED CHANGES IN VALPROIC ACID RELATIVE CLEARANCE IN MAN BY SIMPLE PHARMACOKINETIC SCREENING

Selecting the optimum dose of valproic acid is difficult because the p harmacokinetics are complicated by interpatient variability and by eff ects arising as a result of co-administration with other antiepileptic drugs. The multiple peak approach has been used to evaluate the effec t of age, total body weight, dose, gender and comedication (carbamazep ine-induced change) on population estimates of valproic acid relative clearance. Routine clinical pharmacokinetic data (n = 479) were collec ted from 207 epilepsy patients on combination therapy. The data were a nalysed by a simple steady-state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic an alysis that enables pooling of data. NONMEM estimates suggested that t he rate of valproic acid clearance in patients receiving concomitant a dministration of valproic acid and carbamazepine decreased non-linearl y with increasing total body weight in the maturation process, and inc reased non-linearly with increasing valproic acid dose. The clearance in females was 5.7% less than in males. NONMEM estimates also suggeste d that the rate of valproic acid clearance increased nonlinearly with increasing carbamazepine dose. Concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs resulted in an i ncrease in valproic acid clearance of 10%. The final regression model of valproic acid relative clearance was CL=6.06TBW(-0.168) x DOSE0.414 x CBZDOSE(0.095) x 0.943(GEN) x 1.10(CO), where CL is the clearance ( mL kg(-1) h(-1)), TBW is the total body weight (kg), DOSE is the dose of valproic acid, CBZDOSE is the dose of carbamazepine, GEN = 0 for ma les and 1 for females and CO = 0 for concomitant administration of val proic acid and carbamazepine and 1 for concomitant administration of v alproic acid and carbamazepine with other antiepileptic drugs. This te chnique can be used to estimate the pharmacokinetic parameters of a po pulation from sparse data collected during routine clinical care and t o determine the extent to which patient characteristics influence drug pharmacokinetics.