Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics.

Nirmatrelvir/ritonavir (N/R) is one of the most effective antiviral drugs against SARS-CoV-2. The preclinical development, pharmacodynamics and pharmacokinetics of N/R are reviewed herein. Randomized clinical trials have been conducted exclusively with pre-Omicron variants of concern, but in vitro studies show that efficacy against all Omicron sublineages is preserved, as confirmed by post-marketing observational studies. Nevertheless, investigations of large viral genome repositories have shown that mutation in the main protease causing resistance to N/R are increasingly frequent. In addition, virological and clinical rebounds after N/R discontinuation have been reported in immunocompetent patients. This finding is of concern when translated to immunocompromised patients, in whom N/R efficacy has not been formally investigated in clinical trials. Economical sustainability and perspectives for this therapeutic arena are discussed.