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Updated: Jun 12, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Drug-drug interactions of simnotrelvir/ritonavir: an open-label, fixed-sequence, two-period clinical trial
Pan-Pan Ye1, Bu-Fan Yao2, Yang Yang3
1Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China.
Objectives:
Simnotrelvir is a small-molecule highly specific 3C-like protease inhibitor for anti-SARS-CoV-2 and was approved as a combination drug with ritonavir (simnotrelvir/ritonavir) in China. Simnotrelvir is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), and a weak inhibitor of CYP3A. Ritonavir is a substrate and inhibitor of CYP3A and an inhibitor of P-gp. Hence, the drug-drug interaction potential of simnotrelvir/ritonavir should be investigated.
Methods:
This drug-drug interaction study was an open-label, fixed-sequence, two-period phase I clinical trial in Chinese healthy adult subjects, divided into three cohorts, including simnotrelvir/ritonavir co-administrated with a strong CYP3A and P-gp inhibitor (itraconazole) and inducer (rifampicin), and with a specific CYP3A substrate (midazolam).
Results:
The results demonstrated that compared with administration of simnotrelvir/ritonavir alone, the co-administration with itraconazole increased the geometric least-square mean ratio (GMR) of the expose (area under the plasma concentration-time curve from time zero to the lowest detectable plasma concentration [AUC0-t]) of simnotrelvir by 25% (GMR 125%, 90% CI 114-137%), whereas co-administration with rifampicin significantly decreased the AUC0-t of simnotrelvir by 81.5% (GMR 18.5%, 90% CI 16.4-20.9%). Notably, simnotrelvir/ritonavir increased the AUC0-t of midazolam by 16.69-fold (GMR 1769%, 90% CI 1551-2018%). The co-administration of simnotrelvir/ritonavir and rifampicin caused the increased amount and severity of treatment-emergent adverse events, especially hepatotoxicity.
Discussion:
The co-administration of simnotrelvir/ritonavir with CYP3A and P-gp inhibitors can be safely used, whereas the co-administration with CYP3A and P-gp strong inducer should be avoided to minimize the risk of under-exposure. Co-administration of midazolam with simnotrelvir/ritonavir increased systemic exposure of midazolam.
Clinicaltrials:
gov Identifier: NCT05665647.
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