Assessing Cytochrome P450 Drug Interaction Risk for Dordaviprone Using Physiologically Based Pharmacokinetic Modeling.

Abstract

A physiologically based pharmacokinetic (PBPK) model was developed and verified for dordaviprone, a small molecule with antitumor effects in glioma patients. The model was applied to assess the drug-drug interaction (DDI) potential of dordaviprone as a victim of CYP3A4 inhibitors and inducers, and as a perpetrator of CYP3A4, CYP2C8, CYP2D6 inhibition. A combination of in vitro and clinical data was used to develop a minimal distribution PBPK model with a single adjusting compartment and mechanistic absorption using the Simcyp Population-Based Simulator (V21). Simulated maximum concentration (Cmax) and area under the concentration time curve (AUC) of the 3 clinical studies used to verify the PBPK model were within 1.4-fold of observed exposures. The simulated increase in dordaviprone AUC and Cmax (4.6- and 1.7-fold) following administration of multiple doses of itraconazole was consistent with the observed values (4.4- and 1.9-fold). All PBPK-simulated changes in dordaviprone plasma exposure when administered with CYP3A4 moderate (erythromycin, fluconazole) and weak (cimetidine) inhibitors, and moderate (efavirenz) and strong (rifampicin) inducers were consistent with their CYP3A4 potency classification (AUC ratio = 2.68, 2.48, 1.42, 0.35, and 0.17, respectively). The simulated AUC and Cmax of probe substrates for CYP3A4 (midazolam), CYP2C8 (repaglinide) and CYP2D6 (desipramine) after coadministration with 625 mg dordaviprone were the same as those in the absence of dordaviprone (ratio = 1.0) and remained unchanged after a sensitivity analysis using 10-fold more potent inhibition constants. Due to changes in dordaviprone plasma exposure when co-administered with CYP3A4 inhibitors, dordaviprone dose adjustments may be necessary; CYP3A4 inducers should be avoided.