A Model for Estimating Individualized Valproate Clearance Values in Children

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Abstract
To evaluate the population pharmacokinetics of valproic acid in children, 97 steady‐state serum valproate concentration measurements were gathered during normal, routine, outpatient care of 52 children with epilepsy (1.2–16 years of age). Levels were obtained from patients receiving valproate monotherapy (49%) or valproate with concomitant carbamazepine (32%), phenytoin (11%), or phenobarbitone (8%). A one‐compartment model was used to fit the data with the Nonlinear Mixed Effects Model (NONMEM) computer program. The final model for clearance (L/hr) was CL = [EXP (0.022WT − 1.38)] × M, where EXP = the base of the natural logarithm, WT = patient weight (kg) and M = a scaling factor for concomitant medication with a value of 1 for patients on valproate monotherapy and 1.61 for those receiving concomitant carbamazepine. Although phenytoin and phenobarbitone also were expected to increase valproate clearance, this could not be demonstrated, possibly because of the small number of samples taken from patients receiving these agents. Weight‐adjusted values of valproate clearance decreased with increasing age. The actual mean value of 0.021 L/hr/kg for children taking monotherapy was slightly higher than values shown in most previously published reports, whereas the mean value of 0.028 L/hr/kg for patients taking concomitant carbamazepine was similar to those found previously in children taking other antiepileptic drugs.