Valproic acid physiological pharmacokinetics simulation for epilepsy patients via a refined seven-compartmental model: A pilot study

Abstract

This study simulated valproic acid (VPA) physiological pharmacokinetics for epilepsy patients via a refined seven-compartmental model. The seven compartments were defined as oral, GI Tract, liver, whole body (WB), cerebrospinal fluid (CSF), kidney, and bladder. A first-order system of seven differential equations was defined according to this specific model and solved by a self-developed program run in MATLAB to evaluate the VPA time-dependent change among compartments. Each compartment's preset dissolving half-life (in hours) was as follows: oral 0.05, GI Tract 0.10, liver 0.5, WB 2.2, CSF 0.8, kidney 1.2, and bladder 0.5, respectively. The derived results were reorganized according to various presets of dissolving half-lives of the liver, WB, CSF, or kidney to analyze the VPA time-dependent changes under various scenarios. Either the liver or WB was the dominant compartment in this model, which mainly controlled the VPA changes. In contrast, others compartments followed the principle of secular equilibrium in the chain decay of radioactive nuclides. Accordingly, the VPA degradation changes in WB (“mother” compartment) mainly affected the VPA changes in other (“daughter”) compartments. Thus, the predicted VPA degradation in CSF, kidney, or bladder was always longer than in WB despite its dissolving half-life changes. The predicted results of VPA changes in various compartments were also compared with other studies, and a reasonable agreement was reached on whether the dissolving half-life of the liver or WB ranged from the original 0.2/2.2 to 1.4/0.9 h. The programable capability of this self-developed program allows one to easily modify the primary preset to comply with findings from other studies and has great potential in similar applications.