Background and Objectives <p>Preclinical studies have shown that leritrelvir, an anti-coronavirus disease 2019 (COVID-19) drug, is a substrate of CYP3A and P-gp. It also inhibits CYP3A, CYP2C19, and OATP1B3. This study systematically evaluated leritrelvir’s pharmacokinetic interactions with sensitive substrates, inhibitors, or inducers of the aforementioned metabolic pathways. The short-term safety of co-administration was also assessed.</p> Methods <p>We conducted a phase Ⅰ, single-arm, open-label, dual-cohort clinical trial in healthy Chinese adults. Cohort 1 evaluated the effect of multiple doses of leritrelvir on the pharmacokinetics of midazolam, omeprazole, and rosuvastatin. Serial blood samples were collected for the determination of midazolam and omeprazole concentrations at pre-dose and post-dose on days 1–2 (midazolam and omeprazole alone) and days 10–11 (midazolam and omeprazole co-administered with leritrelvir). For rosuvastatin, blood samples were collected at pre-dose and post-dose on days 3–6 (rosuvastatin alone) and days 12–15 (rosuvastatin co-administered with leritrelvir). Cohort 2 assessed the effect of multiple dose administration of verapamil and rifampicin on the pharmacokinetics of leritrelvir. Serial blood samples were collected for the determination of leritrelvir concentrations at pre-dose and post-dose on days 1–4 (leritrelvir alone), days 9–12(leritrelvir co-administered with verapamil), and days 28–31(leritrelvir co-administered with rifampicin).</p> Results <p>In cohort 1, leritrelvir minimally affected omeprazole and rosuvastatin exposure. The geometric mean ratios (GMRs) for their area under the plasma concentration–time curve from time zero to the lowest detectable plasma concentration (AUC_0–t) were 98.3% and 113.2%, respectively, versus administration alone. In contrast, leritrelvir increased midazolam AUC_0–t to 232.1% (GMR) versus administration alone. In cohort 2, verapamil increased leritrelvir AUC_0–t to 251.8% (GMR) versus administration alone. Rifampicin decreased leritrelvir AUC_0–t to 80.6% (GMR).</p> Conclusions <p>The potential for drug–drug interactions between leritrelvir and CYP2C19 or OATP1B3 is low. The same applies to its interaction with a CYP3A inducer. However, as a moderate CYP3A inhibitor, leritrelvir requires caution when co-administered with CYP3A substrates, especially those with a narrow therapeutic index. Although moderate inhibitors of CYP3A and P-gp increased the leritrelvir exposure, this increase may not require dose adjustment on the basis of the phase I PK data of leritrelvir.</p> Clinicaltrials.gov Identifier <p>NCT06031454.</p>