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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

Year: 2025

Type: article

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 (AUC0‐inf) and maximal drug concentration (Cmax) based on the model were generally within 2‐fold of observed values for all soticlestat doses. Model‐simulated versus observed AUC0‐inf and Cmax 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 AUC0‐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.

Source: Clinical Pharmacology in Drug Development

DOI: 10.1002/cpdd.1526