Pharmacological and safety evaluation of an anti-viral drug, nirmatrelvir

<p>[Background] Nirmatrelvir is a potent and selective inhibitor of the SARS-CoV-2 Main protease, administered as an oral agent for the treatment of COVID-19 patients in combination with a low dose of ritonavir. Ritonavir inhibits the CYP3A4-mediated metabolism of nirmatrelvir in humans, thereby providing increased and sustained plasma concentrations of nirmatrelvir.</p><p>[Pharmacological evaluation] The primary pharmacodynamic properties of nirmatrelvir were evaluated in a series of in vitro enzymatic and viral cell culture assays. In in vivo study using a mouse-adapted virus, SARS-CoV-2-MA10, inoculated intranasally in mice, the anti-viral effect of nirmatrelvir was confirmed. Combination of nirmatrelvir and ritonavir demonstrated improved efficacy and lung tissue protection compared to nirmatrelvir or ritonavir alone. </p><p>[Safety evaluation] Nonclinical toxicity studies of nirmatrelvir were conducted in accordance with ICH M3(R2). The NOAELs were the highest dose in general toxicity studies using rat or monkey. The results of genotoxicity studies were negative. Nirmatrelvir had no adverse effects on male or female fertility in rats, fetal morphology or embryo-fetal viability in rats and rabbits, or PPND in rats. No combination toxicity studies of nirmatrelvir with ritonavir were conducted because no overlapping or additive toxicities are expected. </p><p>[Conclusion] From these results, nonclinical toxicology package adequately supports the marketing application of nirmatrelvir in combination with ritonavir for the intended clinical usage.</p>