Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions of Soticlestat as a Victim of CYP Induction and Inhibition, and as a Perpetrator of CYP and P-Glycoprotein Inhibition.

Abstract

Soticlestat (TAK-935) is a cholesterol 24-hydroxylase inhibitor. A physiologically-based pharmacokinetic model has been developed to predict potential soticlestat drug-drug interactions (DDIs) using the Simcyp v20 Population-based Simulator and verified with data from single-/multiple-rising-dose and clinical DDI studies. Simulated area under the plasma concentration-time curve from 0 to infinity (AUC_0-inf) and maximal drug concentration (C_max) based on the model were generally within 2-fold of observed values for all soticlestat doses. Model-simulated versus observed AUC_0-inf and C_max geometric mean ratios (GMRs) for soticlestat with/without itraconazole (potent cytochrome P450 [CYP] 3A inhibitor), and mefenamic acid (potent UDP glucuronosyltransferase [UGT] 1A9 inhibitor) were ≤1.10-fold. As soticlestat is primarily metabolized by UGT enzymes and Simulator v20 incorporates rifampin's induction of CYP3A only, the model underpredicted soticlestat's DDI with rifampin. However, with user-defined rifampin UGT induction, the predicted AUC_0-inf GMR was within 1.5-fold of the observed value, meeting the 2-fold acceptance criteria. Hence, the model was appropriate for evaluating DDIs with CYP3A inhibitors and inducers not evaluated in clinical DDI studies; all predicted DDIs were low/not clinically relevant (<50% impact on exposure). Furthermore, no clinically significant DDIs were predicted following coadministration of soticlestat with sensitive CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-glycoprotein substrates.