Developing pharmacokinetics–pharmacodynamics model of valproic acid syrup based on prediction of population pharmacokinetics parameter and seizure frequency in Indonesian pediatric epilepsy outpatients

Abstract

Abstract Objectives Valproic acid (VPA) is a broad-spectrum antiepileptic drug with known efficacy profile in pediatric patients, despite of its narrow therapeutic index. There is lack of VPA’s pharmacokinetics profile in Indonesian pediatric subjects, partly due to limited pediatric blood volume taken for conducting therapeutic drug monitoring. This study aimed to determine the correlation between VPA pharmacokinetics parameters based on population data and seizure frequency in pediatric epilepsy outpatients. Methods This observational study was conducted at Sanglah General Hospital during June–December 2019. The subjects of this research were 38 pediatric epilepsy patients who adhered to VPA syrup monotherapy for at least 3 weeks. Five subjects randomly selected for blood sample collection. Thus, VPA concentration level in the blood being analysed as a comparison to its concentration predicted from Yukawa’s steady state equation. Monolix2019R2® software was used to identify VPA population pharmacokinetics–pharmacodynamics (PK–PD) parameters at steady state level. Results Population PK–PD of VPA syrup at steady state level were ka_pop = 6.25/h, Vd_pop = 3.36 L, Cl_pop = 3.17·e−11 mL/min, IC50_pop = 1.85·e−6, correlation of Vd_pop and Cl_pop = 0.966. Kendall Tau Correlation of predicted VPA steady state concentration and frequency of seizure was −0.66. Mean prediction error between predicted steady state concentration of five subjects and their related blood levels was ≤25% and considered as within clinically acceptable limit. Conclusions It needs further study to develop best matched PK–PD model of VPA syrup at steady state condition in pediatric epilepsy.