A Model for Estimating Individualized Valproate Clearance Values in Children

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)] X 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.

Population pharmacokinetic of antiepileptic drugs in different populations

“…The linear relationship of TBW and age with CL of valproate was shown in the study. The facts that age and total body weight are the important factors that influence a change of VPA CL in children and also in heterogeneous patient populations were in accordance with reports of other authors [15][16][17].…”

“…In agreement with our findings, results of numerous studies have shown that the relative clearance of valproate is increased in concomitant therapy with carbamazepine [15][16][17][18][19]. In children the increase in VPA clearance ranged from 35.9% to 61% [16,18].…”

“…Total body weight is an important cause of interindividual variability of pharmacokinetics of valproate, particularly in the children populations. The significant influence of this factor has been confirmed in studies by other authors that reports point to the possibility of both linear and non-linear increase in VPA clearance with increasing body weight of patients in different populations [15,16,[18][19][20][21]. Also, numerous studies have showed the existence of a linear increase of VPA clearance with body weight in mixed populations of children and adults [6,22].…”

“…Some researchers explained an increasing clearance of VPA with age in the children population in correlation to developmental changes in hepatic drug metabolism [6,17]. There is a very close correlation between total body weight and age of the patient, especially in the children population, but also in heterogeneous populations [6,16]. However, our research clearly showed that the age within the subpopulations of children and adults was not important characteristic that influenced the clearance of valproate which is in accordance with reports by other authors [15,[18][19][20]23].…”

“…In children the increase in VPA clearance ranged from 35.9% to 61% [16,18]. El Desoky et al have shown that influence of carbamazepine was +0.151 lh -1 in a population with equal number of children and adults [17].…”