Estimation of apparent clearance of valproic acid in adult Saudi patients

Background Valproic acid is one of several antiepileptic medications requiring therapeutic drug monitoring due to its complex and wide pharmacokinetic interindividual variability. Objective The objective of this study was to determine the population pharmacokinetics of valproic acid in adult Saudi patients and to identify factors that explain its pharmacokinetic variability. Setting Tertiary referral teaching hospital, Riyadh, Saudi Arabia. Method A retrospective chart review was performed at King Saud University Medical City of patients who received oral valproic acid. The population pharmacokinetic models were developed using Monolix 4.4. After development of the base model, we investigated several covariates including age, sex, weight, total daily dose, and cotherapy with carbamazepine and phenytoin. Main outcome measures the pharmacokinetic parameters of valproic acid and the variables that contributing towards its inter-individual variability. Results The analysis included a total of 54 valproic acid plasma concentrations from 54 patients (42.5% male). The data were sufficiently described by a one-compartment model with linear absorption and elimination processes. Average parameter estimates for valproic acid apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.14 L/h and 37.7 L (fixed), respectively. The inter-individual variability (coefficients of variation) in CL/F was 12%. The most significant covariates for valproic acid CL/F were age, body weight, total daily dose, and cotherapy with carbamazepine and phenytoin. Conclusion This model showed significant inter-individual variability between subjects. Our findings showed that patient age, body weight, total daily dose, and cotherapy with carbamazepine and phenytoin are the most significant covariates of valproic acid clearance. Collectively, healthcare providers should take these factors in consideration for optimal valproic acid dosage regimen.