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Abstract Details

Soticlestat in Vitro Metabolism and Drug-drug Interactions: Comprehensive Investigations Display Minimal Notable Interactions
Epilepsy/Clinical Neurophysiology (EEG)
P9 - Poster Session 9 (8:00 AM-9:00 AM)
1-012
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.
To provide information on metabolism of soticlestat (TAK-935) and any potential drug-drug interactions (DDIs).
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.
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.
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.
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