A MODEL FOR ESTIMATING INDIVIDUALIZED VALPROATE CLEARANCE VALUES IN CHILDREN

To evaluate the population pharmacokinetics of valproic acid in childr en, 97 steady-state serum valproate concentration measurements were ga thered during normal, routine, outpatient care of 52 children with epi lepsy (1.2-16 years of age). Levels were obtained from patients receiv ing valproate monotherapy (49%) or valproate with concomitant carbamaz epine (32%), phenytoin (11%), or phenobarbitone (8%). A one-compartmen t model was used to Ft the data with the Nonlinear Mixed Effects Model (NONMEM) computer program. The final model for clearance (L/hr) was C L = [EXP (0.022WT - 1.38)] X M, where EXP = the base of the natural lo garithm, WT = patient weight (kg) and M = a scaling factor for concomi tant medication with a value of 1 for patients on valproate monotherap y and 1.61 for those receiving concomitant carbamazepine. Although phe nytoin and phenobarbitone also were expected to increase valproate cle arance, this could not be demonstrated, possibly because of the small number of samples taken from patients receiving these agents. Weight-a djusted values of valproate clearance decreased with increasing age. T he actual mean value of 0.021 L/hr/kg for children taking monotherapy was slightly higher than values shown in most previously published rep orts, whereas the mean value of 0.028 L/hr/kg for patients taking conc omitant carbamazepine was similar to those found previously in childre n taking other antiepileptic drugs.