Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

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.

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™

“…26 Collectively, these assessments demonstrate the favorable toxicity profile of nirmatrelvir with a sufficient therapeutic window based on exposure margins using the NOAEL in the repeated dose toxicity studies of 11×/8.0× (C max /AUC 24 ) and 21×/14× (C max /AUC 24 ) for rats and monkeys, respectively, over predicted human therapeutic exposures. The reproductive safety of nirmatrelvir has been demonstrated in dedicated nonclinical developmental and reproductive studies, 43 and it is worth noting that nirmatrelvir did not negatively impact the reproductive organs based on macroscopic and microscopic evaluations in the rat and monkey toxicology studies.…”

Synthesis and Biochemical Evaluation of 8H-Indeno[1,2-d]thiazole Derivatives as Novel SARS-CoV-2 3CL Protease Inhibitors

“…All synthesized compounds were evaluated for inhibitory activity against SARS-CoV-2 3CL pro using PF-07321332 as positive control [ 29 , 30 , 31 ], and the results were detailed in Table 1 . We initially prepared 7a from the commercially available compound 5a by the route outlined in Scheme 1 .…”

Paxlovid: Mechanism of Action, Synthesis, and In Silico Study

“…Then, TFA was added to a 0 °C solution of (10) was utilized without more purification in the next step. In the following, a 0 °C mixture of ( 14), (15), and DMF was treated with HATU. Then, stirring was continued after the addition of DIEA (for 2 h at 0 °C).…”

“…Nirmatrelvir resulted by some modification of tripeptide protein mimetic of lufotrelvir that makes it useful for oral administration [4]. The oral form of nirmatrelvir/ritonavir offers the most promising therapeutic effect compared to these novel medicines (89% reduced risk of hospitalization or death) [12][13][14][15][16] (Figure 1). Nirmatrelvir/ritonavir is expected to reverse the COVID-19 pandemic [17][18][19].…”