Abstract CT176: Pharmacokinetics (PK) of the novel nonsteroidal CYP11A1 inhibitor opevesostat (ODM-208/MK-5684): Interaction potential with midazolam and effect of food
Authors: Natalie Cook, Jan de Hoon, Arif Hussain, Robert H. Jones, Robert J. Jones, Alice Bernard-Tessier, Ruiyang Yan, Magdalena Meissner, Tarja Naukkarinen, Jonathan Belman, Zhiqing Xu, An Bautmans, Aubrey Stoch, Virpi Mononen, Pasi Pohjanjousi, Chris Garratt, Christian Poehlein, Karim Fizazi
Journal: Cancer Research (2025)

Abstract Background: Opevesostat is an oral, nonsteroidal small molecule that selectively inhibits the mitochondrial cholesterol side-chain cleavage enzyme cytochrome P450 11A1 (CYP11A1). In vitro, the active metabolite M1 of opevesostat showed a time-dependent inhibition of CYP3A4. It is crucial to investigate factors that may influence the PK of this novel drug. We present two such PK analyses: first, opevesostat’s potential drug-drug interaction (DDI) with midazolam (a sensitive CYP3A4 substrate) in a dedicated cohort of the phase 1/2 CYPIDES trial in participants (pts) with previously treated metastatic castration-resistant prostate cancer (mCRPC); and second, the effect of food in healthy pts in the open-label, 2-period crossover, single-dose, single-site phase 1 5684-007 study. Methods: In the DDI cohort of CYPIDES, 14 males with progressive mCRPC received oral midazolam 1 mg 1 day before and again 7 days after continuous opevesostat 5 mg BID dosing. In the 5684-007 study, 14 healthy males were allocated to receive a single dose of opevesostat 5 mg after a high-fat meal (n=7) or in a fasted state (n=7). After a ≥7-day washout period, pts crossed over to the opposite treatment. Safety was monitored in both studies. Validated liquid chromatography-tandem mass spectrometry of blood samples was used to determine midazolam and opevesostat concentrations. All PK parameters were calculated by a noncompartmental method. The effect of opevesostat on Cmax, AUCt and AUCinf of midazolam and the effect of food on Cmax, AUCinf and AUClast of opevesostat are presented as geometric mean ratios (GMR; 90% CI). Results: Among pts with mCRPC, midazolam PK were not altered by opevesostat. The AUCs had similar ratios between midazolam with opevesostat vs midazolam alone, with a GMR for AUCt of 0.88 (90% CI 0.75-1.03) and for AUCinf of 0.85 (90% CI 0.72-1.00). For Cmax, the GMR was 0.92 (90% CI 0.73-1.16). Among healthy pts, food did not affect the total exposure to opevesostat. The GMR for fed vs fasted state was 0.97 (90% CI 0.93-1.02) for AUCinf and 0.97 (90% CI 0.92-1.02) for AUClast. A high-fat meal was associated with a decrease in Cmax, with a GMR for fed vs fasted state of 0.59 (90% CI 0.52-0.68), and a delay in median Tmax from 0.50 hr to 2.00 hr. In both studies, opevesostat plasma concentration-time profiles and PK parameters were consistent with previous results. Safety findings in both cohorts were consistent with previous experience. Conclusions: Opevesostat and its metabolite M1 did not inhibit CYP3A4-mediated metabolism and can be safely co-administered with other drugs metabolized through this pathway. Total exposure for opevesostat was not impacted by food. A decrease in opevesostat Cmax and delay in Tmax with a high-fat meal was not unexpected; this observation is unlikely to impact clinical practices around opevesostat administration. Citation Format: Natalie Cook, Jan de Hoon, Arif Hussain, Robert H. Jones, Robert J. Jones, Alice Bernard-Tessier, Ruiyang Yan, Magdalena Meissner, Tarja Naukkarinen, Jonathan Belman, Zhiqing Xu, An Bautmans, Aubrey Stoch, Virpi Mononen, Pasi Pohjanjousi, Chris Garratt, Christian Poehlein, Karim Fizazi. Pharmacokinetics (PK) of the novel nonsteroidal CYP11A1 inhibitor opevesostat (ODM-208/MK-5684): Interaction potential with midazolam and effect of food [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT176.