Nirmatrelvir is an inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing polyprotein precursors, preventing viral replication.

Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay at concentrations achievable in vivo. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography.

Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

This medication is recommended. It is has been granted an emergency use authorization by FDA for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Nirmatrelvir/ritonavir should be initiated as soon as possible after diagnosis of COVID-19 and within five days of symptom onset.

Recommendations are based on EPIC-HR, a Phase2/3 randomized clinical control trial assessing the efficacy of nirmaltrelivir/ritonavir vs. placebo in reduction of hospitalization and or death through day 28. The use of nirmaltrelivir/ritonavir within 5 days of symptom onset in individuals at risk for progression to severe disease reduced the relative risk of hospitalization or death through 28 days by 88%.