Formulation of personalized dosage regimen based on population pharmacokinetics of valproic acid

LI Xin-gang; ZHU Yue-ting; YU Ke-fu; TIAN De-qiang; LIU Wei; ZHAO Zhi-gang

Abstract：Objective:To establish population pharmacokinetics of valproic acid (VPA) in children with epilepsy, and realize personalized dosage regimen on the basis of population pharmacokinetics.Methods:The clinical data and VPAplasma concentrations of children with epilepsy in our hospital from May 2011 to May 2013 were collected retrospectively, and nonlinear mixed effect modeling (NONMEM) method was used to establish population pharmacokinetics of VPA. A one compartment pharmacokinetic model with first-order absorption and elimination was used to characterize the concentration-time data. The first order conditional estimation with η-ε interaction (FOCE-I) was used throughout the model building procedure. Absorption rate constant (ka) was fixed as 2.38 (h-1) according to previous report. On the basis of basic model, the influence of physiological factors and combined medication on relative clearance (CL/F) and apparent volume of distribution (V) were investigated using NONMEM program. Based on the final population pharmacokinetics and Bayesian method, the personalized dosage regimen was optimized. Results:A total of 113 pediatric inpatients and 205 plasma VPA concentrations were collected retrospectively. Objective function value of basic model and final model were 1 555.949 and 1 467.999, respectively. The final population parameters were as follow:CL/F = 0.13 + 0.02 × Age + 0.04 × LTG (L·h-1),V/F = 7.40 + 23.4 × Tablet (L),ka = 2.38 (h-1). Where LTG was 1 when co-medicated with lamotrigine, otherwise LTG was 0. Where Tablet was 1 when patient took VPA tablets, otherwise Tablet was 0. A reliable results were got when using these parameters to predict the drug concentrations.Conclusion:The population pharmacokinetic model was proposed to estimate the individualCL/F andV for pediatric patients receiving VPA.