To develop a physiologically based pharmacokinetic (PBPK) model to predict potential drug–drug interactions (DDIs) of soticlestat (TAK-935).

Soticlestat (in phase 3 development for adjunctive treatment of seizures in Dravet and Lennox–Gastaut syndromes), is metabolized via UGT2B4, UGT1A9, and CYP3A. In vitro, soticlestat is an inhibitor of CYP2C8, CYP2C9, CYP2C19, CYP3A4 and P-glycoprotein (P-gp).

The PBPK model was developed using in vitro and clinical data, verified using clinical data, and applied to evaluate soticlestat as a victim of CYP inhibition and induction, and as a perpetrator of CYP and P-gp inhibition. All analyses were completed using the Simcyp^TM v20 Population-Based Simulator.

Simulated area under the plasma concentration–time curve from time zero to infinity (AUC_0-inf) and maximal drug concentration (C_max) based on the final PBPK model for all doses evaluated were within 2-fold of observed values from single- and multiple-rising-dose studies. For soticlestat 300 mg, the model-simulated AUC_0-inf and C_max geometric mean ratios (GMRs) were 0.88 and 0.78-fold of the observed values, respectively. For soticlestat administered with and without itraconazole (strong CYP3A4 inhibitor), the model-simulated versus observed AUC_0-inf and C_max GMRs were 1.05 and 1.10-fold, respectively. For soticlestat with and without coadministration of rifampin (strong CYP3A4 inducer), the model under-predicted the DDI, with simulated AUC_0-inf and C_max GMRs of >2.9-fold of observed values.

For soticlestat, the model predicted: a weak interaction with strong CYP3A4 inhibition; no interactions with moderate/weak CYP3A4 inhibitors; weak-to-moderate interactions with strong CYP3A4 inducers; and a weak interaction with moderate CYP3A4 inducers. No clinically significant DDIs were predicted following administration of multiple doses of 300 mg twice-daily soticlestat with sensitive CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-gp substrates.

Our verified PBPK model reasonably predicted DDIs and will support the clinical development of soticlestat and regulatory submissions.