A Comprehensive Pharmacological and Clinical Monograph on Nirmatrelvir (PF-07321332)

1.0 Executive Summary

Nirmatrelvir is an orally bioavailable, small-molecule antiviral agent developed by Pfizer that functions as a potent, reversible covalent inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). This enzyme is essential for viral replication, and its inhibition effectively halts the viral life cycle. To overcome rapid metabolic clearance and achieve therapeutic plasma concentrations, nirmatrelvir is co-packaged and co-administered with a low dose of ritonavir, a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme. This combination product is marketed under the brand name Paxlovid.

Developed in response to the urgent global need for an effective outpatient treatment for coronavirus disease 2019 (COVID-19), nirmatrelvir represents a significant milestone in antiviral therapy. Pivotal clinical trials, most notably the EPIC-HR study, demonstrated robust efficacy in non-hospitalized, high-risk adult patients with mild-to-moderate COVID-19. When initiated within five days of symptom onset, treatment resulted in an 88% reduction in the risk of progression to severe disease, including hospitalization or death. This profound clinical benefit led to its rapid deployment worldwide, initially under Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA) in December 2021, followed by full approval in May 2023. A similar accelerated pathway was followed by the European Medicines Agency (EMA).