No effect of co-administered antiepileptic drugs on in-vivo protein binding parameters of valproic acid in patients with epilepsy

Objectives The aim of this study was to establish the population protein binding parameters of valproic acid (VPA) in patients with epilepsy receiving VPA monotherapy and those receiving VPA combined with other antiepileptic drugs. Methods One hundred and thirty nine data sets from 63 Japanese patients with epilepsy were analysed. These patients were separated into two groups: VPA monotherapy and VPA combined with other binding‐sensitive antiepileptic drugs, including phenytoin, clonazepam, clobazam, carbamazepine and phenobarbital (VPA polytherapy). The population protein‐binding parameters of VPA were obtained by non‐linear least‐squares method in each group. Key findings The mean (95% confidence interval) dissociation constants were 38.9 µm (33.2–44.6 µm ) and 36.9 µm (26.7–47.1 µm ), and the numbers of binding sites were 1.36 (1.27–1.44) and 1.33 (1.19–1.47) in the monotherapy and polytherapy groups, respectively. No significant differences in the binding parameters of VPA to serum albumin were observed between the two groups. Conclusions The steady‐state serum albumin binding of VPA in Japanese patients with epilepsy is not affected by co‐administration of other antiepileptic drugs. These findings suggest that serum VPA concentration is stable at the steady state with regard to interaction by protein binding, even when other antiepileptic drugs with moderate‐to‐high binding properties are co‐administered.