PII-164 - ASSESSING CYTOCHROME P450 DRUG INTERACTION RISK FOR ONC201 USING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING

S. Jaiswal¹, N. Patel¹, H. Jones², S. McFeely¹, S. Faison³, T. Tippin⁴, O. Naderer⁴; ¹Certara Simcyp Division, Certara Inc., ²Certara UK Limited, Simcyp Division, ³Certara Strategic Consulting, ⁴Chimerix, Inc..

Background: ONC201 (dordaviprone) is a novel orally administered, small molecule imipridone, with demonstrated antitumor effects in glioma patients. CYP3A4 is a key elimination pathway for ONC201 accounting for >50% of its clearance. In vitro inhibition of CYP3A4, CYP2C8, CYP2D6 by ONC201 suggests potential for clinical interaction. A physiologically based pharmacokinetic (PBPK) model was constructed for ONC201 to evaluate the ONC201 drug-drug interaction (DDI) potential as a victim of CYP3A4 modulation, and as a perpetrator of CYP3A4, CYP2C8, CYP2D6 inhibition.

Methods: A combination of in vitro and clinical data was used to develop the PBPK model using Simcyp™ Population-Based Simulator (V21). The ONC201 fraction metabolized by CYP3A4 was set at 0.8 based on the observed data from an itraconazole DDI study in healthy adults. Model verification was performed by comparing model-simulated PK profiles to observed values, with acceptance criteria set to < 2-fold difference. The verified PBPK model was applied to evaluate the change in ONC201 PK after a single 625 mg dose with and without coadministration of (multiple doses) of erythromycin, fluconazole, cimetidine, efavirenz and rifampicin in healthy adults. The model was further applied to simulate the change in PK of midazolam, repaglinide, and desipramine after coadministration with 625 mg ONC201.

Results: Model simulated (S) Cmax and AUC of the 3 clinical studies used to qualify the PBPK model were within 1.4-fold of observed (O) exposures (n=61 subjects). The simulated increase in ONC201 AUC and Cmax following administration of multiple doses of itraconazole was consistent with the observed values (S/O ratios within 1.1-fold; n=18 subjects). All simulated CYP3A4 modulators were predicted to change ONC201 plasma exposure, consistent with their CYP3A4 potency classification (Table 1). The simulated AUCinf and Cmax of probe substrates for CYP3A4, CYP2C8 and CYP2D6 after coadministration with ONC201 were like those in the absence of ONC201 ( < 1.05-fold).

Conclusion: A PBPK model for ONC201 was successfully developed and verified. When co-administered with CYP3A4 inducers and inhibitors, changes in ONC201 plasma exposure were predicted by the model. ONC201 was not predicted to perpetrate an interaction with CYP enzymes.