Soticlestat in Vitro Metabolism and Drug-Drug Interactions: Comprehensive Investigations Display Minimal Notable Interactions
Abstract number :
1.302
Submission category :
7. Anti-seizure Medications / 7E. Other
Year :
2023
Submission ID :
327
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: T Eric Ballard, PhD – Takeda Pharmaceutical Company, Ltd
Lawrence Cohen, BA – Takeda Pharmaceutical Company, Ltd; Yuu Moriya, PhD – Takeda Pharmaceutical Company, Ltd; Mitsuhiro Nishihara, PhD – Takeda Pharmaceutical Company, Ltd; Bei-Ching Chuang, BASc – Takeda Pharmaceutical Company, Ltd; Miyuki Ugajin, MPharm – Takeda Pharmaceutical Company, Ltd; Hideki Hirabayashi, PhD – Takeda Pharmaceutical Company, Ltd; Yoshihiko Tagawa, PhD – Takeda Pharmaceutical Company, Ltd; Junzo Takahashi, MEng – Takeda Pharmaceutical Company, Ltd
Rationale: Soticlestat (TAK-935) is a selective inhibitor of cholesterol 24-hydroxylase in phase 3 development for adjunctive treatment of seizures associated with Dravet and Lennox-Gastaut syndromes. Many preclinical investigations using human cells have been undertaken to provide information on the metabolism of soticlestat and any potential drug-drug interactions (DDIs).
Methods: In vitro investigations for soticlestat metabolism and potential DDIs were conducted in human hepatocytes (HHep), liver microsomes (HLM), embryonic kidney (HEK), and colon adenocarcinoma clone 2 (Caco-2) cells using standard methodology.
Results: In HHep in vitro incubations, soticlestat-glucuronide (TAK-935-G) accounted for 66% of total metabolism after 6h with 34% attributed to cytochrome P450 (CYP). Additional CYP mapping found soticlestat was highly metabolized by CYP3A4-expressing microsomes and slightly metabolized by CYP2C19; however, recent, more accurate phenotyping data showed CYP3A is the only CYP responsible for soticlestat metabolism. Initial UGT enzyme mapping studies found soticlestat glucuronidation was mediated predominately by UGT1A9 and UGT2B4 while later studies in HLMs showed UGT metabolism was almost exclusively UGT2B4 (89.7%; the remainder by UGT1A9). Reversible CYP inhibition studies with soticlestat in HLMs showed notable inhibition of CYP2C8 (half maximal inhibitory concentration, IC50=28 μM), CYP2C9 (IC50=30 μM), CYP2C19 (IC50=18 μM) and CYP3A4 (IC50=30 μM). Due to a high oral dose of soticlestat, potentially clinically relevant interactions were possible for CYP3A4 in the gut and borderline for CYP2C19 systemic interaction, both requiring follow up with physiologically-based pharmacokinetic modelling and/or clinical studies. Soticlestat did not exhibit time-dependent inhibition of any major CYP enzymes in HLM or induce CYP1A2, CYP2B6, or CYP3A4 in HHep. Soticlestat was not found to be a substrate for organic anion transporting polypeptide (OATP) 1B1, OATP1B3 or P-glycoprotein (P-gp) and did not inhibit the common drug metabolizing UGT enzymes (i.e., UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7 and 2B15) or UGT2B4 and UGT2B17 at clinically relevant concentrations. Soticlestat was determined to be a weak inhibitor of OATP1B1 and OATP1B3 mediated transport in HEK cells but based on calculated R values did not show clinically relevant inhibition. In Caco-2 cell monolayers, soticlestat was determined to inhibit P-gp mediated transport (IC50=81.1 µM). TAK-935-G was not an inhibitor of the most common CYP or UGT enzymes or an inducer of CYP2B6 or CYP3A4. CYP1A2 showed minor induction in the presence of TAK-935-G and based on its high circulating concentration, a weak in vivo interaction was calculated with the Basic Model.
Conclusions: Based on these in vitro findings, soticlestat has well-characterized metabolism and limited victim and perpetrator DDI potential leading to minimal concern of clinical DDI risk.
Funding: Takeda Pharmaceutical Company Ltd.
Anti-seizure Medications