Assessment of the impact of valproic acid co-administration on clozapine plasma concentrations in Tunisian patients

OBJECTIVES: Reports on drug-drug interactions between Valproic Acid (VPA) and Clozapine (CLZ) are very inconsistent. Previous reports demonstrate that VPA may exhibit either inhibitory or inductive effects or have no effect on CLZ pharmacokinetics. The aim of this study was to investigate the impact of VPA on plasma CLZ concentrations in a series of Tunisian patients. METHODS: This retrospective study was conducted from 2010 to 2025 at the Clinical Pharmacology Department of the Tunisian National Pharmacovigilance Center and included samples of patients treated by CLZ for schizophrenia. RESULTS: A total of 1,035 samples were analyzed: 814 corresponded to CLZ monotherapy and 221 to combined of VPA and CLZ therapy. The median CLZ plasma concentration-to-dose ratio (C/D ratio) was significantly higher in the monotherapy group than in the combination group (0.87 vs. 0.75 ng/mL per mg/day; p<0.05). Within the combination group, the CLZ C/D ratio was significantly lower in men than in women (0.67 vs. 1.16 ng/mL per mg/day; p<0.05). CONCLUSIONS: Our study demonstrates a significant inductive effect of VPA on CLZ metabolism, which may be influenced by factors such as gender. Hence, clinicians should be aware of the critical need for CLZ monitoring in clinical practice to personalize treatment adjustment.