Abstract Details

Title Soticlestat in Vitro Metabolism and Drug-drug Interactions: Comprehensive Investigations Display Minimal Notable Interactions

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P9 - Poster Session 9 (8:00 AM-9:00 AM)

Poster/Presentation
Number 1-012

Objective To provide information on metabolism of soticlestat (TAK-935) and any potential drug-drug interactions (DDIs).

Background Soticlestat is a selective inhibitor of cholesterol 24-hydroxylase in phase 3 development for adjunctive treatment of seizures associated with Dravet and Lennox-Gastaut syndromes.

Design/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 6 h with 34% attributed to cytochrome P450 (CYP). Phenotyping data showed CYP3A is the only CYP responsible for soticlestat metabolism. Studies in HLMs showed UGT metabolism was almost exclusively UGT2B4 (89.7%; the remainder by UGT1A9). Reversible CYP inhibition studies with soticlestat in HLM showed notable inhibition of CYP2C8 (IC₅₀=28 μM), CYP2C9 (IC₅₀=30 μM), CYP2C19 (IC₅₀=18 μM) and CYP3A4 (IC₅₀=30 μM). 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 common drug metabolizing UGT enzymes or UGT2B4 and UGT2B17 at clinically relevant concentrations. Soticlestat was a weak inhibitor of OATP1B1 and OATP1B3 mediated transport in HEK cells, but calculated R values did not show clinically relevant inhibition. In Caco-2 cell monolayers, soticlestat inhibited 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 Soticlestat has well-characterized metabolism and limited victim and perpetrator DDI potential leading to minimal concern of clinical DDI risk.

Authors/Disclosures
Lawrence H. Cohen (Takeda Pharmaceuticals Inc.) PRESENTER	Mr. Cohen has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Mr. Cohen has stock in Takeda.
Thomas Ballard (Takeda)	No disclosure on file
Yuu Moriya (Takeda Pharmaceutical Company, Ltd.)	No disclosure on file
Mitsuhiro Nishihara	No disclosure on file
Bei-Ching Chuang	No disclosure on file
Miyuki Ugajin	No disclosure on file
Hideki Hirabayashi	No disclosure on file
Yoshihiko Tagawa	No disclosure on file
Junzo Takahashi	No disclosure on file

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