Absorption, distribution, metabolism, and excretion tactics toward the expedited discovery and development of the severe acute respiratory syndrome coronavirus-2 main protease inhibitor nirmatrelvir.

The severe acute respiratory syndrome coronavirus-2 main protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), has been approved by the US Food and Drug Administration as an oral treatment option for coronavirus disease 2019 patients. In this perspective, we share the expediated absorption, distribution, metabolism, and excretion strategies, which were incorporated as part of discovery efforts, to design orally active severe acute respiratory syndrome coronavirus-2 main protease inhibitors. PF-07321332 (nirmatrelvir) emerged as a potential oral clinical candidate within ∼ 6 months from the time discovery efforts were first initiated. The review also delves into a discussion around the successful use of quantitative fluorine-19 nuclear magnetic resonance spectroscopy in the characterization of the human mass balance and excretion pathways of nirmatrelvir. Human absorption, distribution, metabolism, and excretion data that emerged from the fluorine-19 nuclear magnetic resonance study were used to support the Emergency Use Authorization and new drug application filing, which was accepted by regulatory agencies worldwide. Efficient operational and technical strategies, incorporating the elements of speed without sacrificing data quality, which were crucial to the success of the program, are highlighted. SIGNIFICANCE STATEMENT: This perspective discusses the expedited absorption, distribution, metabolism, and excretion efforts utilized in the discovery and development of the orally active severe acute respiratory syndrome coronavirus-2 main protease inhibitor nirmatrelvir, which in combination with the cytochrome P450 3A inhibitor ritonavir (Paxlovid), is used in the oral treatment of COVID-19. Paxlovid was granted an Emergency Use Authorization by global regulatory agencies in less than 2 years from the initiation of the discovery program and has since been fully approved by the US Food and Drug Administration.