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Abstract Details

Physiologically-based Pharmacokinetic Modeling to Predict Drug–drug Interactions of Soticlestat
Epilepsy/Clinical Neurophysiology (EEG)
S29 - Epilepsy Diagnostics and Therapeutics (1:00 PM-1:12 PM)

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).

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

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 SimcypTM v20 Population-Based Simulator.

Simulated area under the plasma concentration–time curve from time zero to infinity (AUC0-inf) and maximal drug concentration (Cmax) 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 AUC0-inf and Cmax 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 AUC0-inf and Cmax 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 AUC0-inf and Cmax 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.

Lawrence Cohen (Takeda Pharmaceuticals Inc.)
Mr. Cohen has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Mr. Cohen has stock in Takeda.
Wei Yin Wei Yin has received personal compensation for serving as an employee of Takeda. Wei Yin has stock in Takeda.
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