Comprehensive in vitro assessment of drug-drug interactions of the major human metabolite of soticlestat

Abstract

Soticlestat (TAK-935) is a selective cholesterol 24S-hydroxylase inhibitor and represents a potential adjunctive treatment for Dravet and Lennox-Gastaut syndromes. The direct glucuronide metabolite of soticlestat TAK-935-G is the primary circulating drug-related material in humans. Thus, the potential of TAK-935-G as a perpetrator for drug-drug interactions (DDIs) was evaluated according to the current regulatory guideline. The DDI risk between soticlestat/TAK-935-G and representative anti-seizure medications (ASMs) was also investigated using various in vitro assays.TAK-935-G was not a perpetrator of cytochrome P450 enzymes (CYPs), uridine diphosphate glucuronosyl-transferase enzymes (UGTs) or transporters, except for CYP1A2 induction, where it demonstrated an induction with an E_max of 2.06- to 3.56-fold change and EC₅₀ of 53.7-78.8 µM. Two ASMs are known to be substrates of CYP1A2; however, no serious DDI through CYP1A2 induction has been reported. The examined ASMs did not inhibit soticlestat glucuronidation. Moreover, soticlestat and TAK-935-G did not inhibit glucuronidation of the examined ASMs.Collectively, no notable concern exists regarding the clinical perpetrator risk of CYP, UGT and transporters with TAK-935-G, despite its high unbound plasma concentrations. The combined analysis of in vitro and clinical DDI results, alongside physiologically based pharmacokinetic modelling, exhibited a low DDI risk for soticlestat and TAK-935-G.

Keywords: anti-seizure medication (ASM); cytochrome P450 (CYP); drug-drug interaction (DDI); glucuronide metabolite; soticlestat; transporter; uridine diphosphate glucuronosyltransferase (UGT).