A Comprehensive Evaluation in Clinic and PBPK Modeling and Simulation to Confirm Lack of CYP450 Mediated Drug-Drug Interaction Potential for Pomotrelvir.

Pomotrelvir is a new chemical entity and potent direct-acting antiviral (DAA) inhibitor of the main protease (M ) of coronaviruses (CoVs). Here the cytochrome P450 (CYP) -mediated drug-drug interaction (DDI) potential of pomotrelvir was evaluated for major CYP isoforms, starting with in vitro assays followed by the basic static model assessment. The identified CYP3A4-mediated potential DDIs were evaluated clinically at a supratherapeutic dose of 1050 mg twice daily (BID) of pomotrelvir, including pomotrelvir co-administration with ritonavir (strong inhibitor of CYP3A4) or midazolam (sensitive substrate of CYP3A4). Further, a physiologically-based pharmacokinetic (PBPK) model was developed within the Simcyp Population-based Simulator using in vitro and in vivo information and validated with available human pharmacokinetic data. The PBPK model was simulated to assess the DDI potential for CYP isoforms that pomotrelvir has shown a weak to moderate DDI in vitro, and for CYP3A4 at the therapeutic dose of 700 mg BID. To support the use of pomotrelvir in women of childbearing potential, the impact of pomotrelvir on the exposure of the representative oral hormonal contraceptive drugs ethinyl estradiol and levonorgestrel was assessed using the PBPK model. The overall assessment suggested weak inhibition of pomotrelvir on CYP3A4 and minimal impact of a strong CYP3A4 inducer or inhibitor on pomotrelvir PK. Therefore, pomotrelvir is not anticipated to have clinically meaningful DDIs at the clinical dose. These comprehensive in vitro, in clinic and in silico efforts indicate the DDI potential of pomotrelvir is minimal so excluding patients on concomitant medicines in clinical studies would not be required.