Abstract
Nirmatrelvir (PF-07321332; NMV) the antiviral component of PAXLOVID™ is a potent and selective inhibitor of the SARS-CoV-2 main protease (M pro ), which plays a critical role in viral replication. PAXLOVID, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. PAXLOVID has been shown to be efficacious against hospitalization and death in two Phase 2/3 clinical studies that evaluated non hospitalized patients both with and without high risk factors for progression to severe illness. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. The results of these nonclinical studies with NMV along with existing ritonavir safety information indicate that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and in males and females of reproductive age.
Keywords: COVID-19; Coronavirus; Embryo-Fetal development; Fertility; Genetic toxicity; NMV; Nirmatrelvir; Oral COVID-19 therapy; PAXLOVID; Rabbit; Rat.
【저자키워드】 COVID-19, coronavirus, Fertility, rabbit, Nirmatrelvir, Paxlovid, Embryo-Fetal development, Genetic toxicity, NMV, Oral COVID-19 therapy, Rat., 【초록키워드】 therapy, Antiviral, Hospitalization, Genetic, Ritonavir, risk, Toxicity, progression, protease, virus, SARS-CoV-2 main protease, Replication, Protein, Pregnancy, viral replication, male, female, death, Clinical studies, age, Fertility, oral, PF-07321332, inhibitor, information, rabbit, Critical, Nirmatrelvir, Paxlovid, pharmacokinetic, clinical study, administration, embryonic development, severe disease, phase, RAT, manifestation, therapeutic target, high risk, therapeutic option, during pregnancy, no effect, specific protein, Factor, female fertility, no effects, RATs, M pro, selective, patient population, mammalian cells, enhancer, Effect, ICH, Prevent, Embryo, limit dose, shown, lack, reported, clinically, evaluated, in viral, hospitalized patient, embryonic, reproductive, developmental, infected with SARS-CoV-2, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, animal model, inhibitor, Nirmatrelvir, developmental,