Innovative Randomized Phase 1 Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir

Abstract

Background: COVID-19 is a continued leading cause of hospitalization and death. Safe and efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, SARS-CoV-2 Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. Methods: We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase 1 study . Two interleaving single-ascending dose (SAD) cohorts were evaluated in a 3-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (BID) dosing was evaluated over 10 days in 5 parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase 2/3 clinical trials were supported by integrating modelling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). Results: In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase 2/3 trials (300/100 mg BID), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients and prevent development of severe disease, hospitalization, and death. Conclusions: An innovative and seamless trial design expedited establishment of phase 1 safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase 2/3 dose selection and accelerated pivotal trials initiation. NCT04756531

Lack of antiviral activity of probenecid in Vero E6 cells and Syrian golden hamsters: a need for better understanding of inter-lab differences in preclinical assays

“…hydroxychloroquine, lopinavir, ivermectin (1-7)) or in various stages of development for other indications (e.g. remdesivir, molnupiravir, nirmatrelvir (8)(9)(10)(11)(12)). The speed at which drugs can be brought forward under the urgency of a pandemic is a significant advantage.…”

Simultaneous determination of nirmatrelvir and ritonavir in human plasma using LC–MS/MS and its pharmacokinetic application in healthy Chinese volunteers

“…Among extraction modes, the protein precipitation method was prioritized for pretreatment due to its simple operation procedure and high plasma concentration of nirmatrelvir and ritonavir (R. S. P. Singh et al, 2022). The method mentioned previously had unparalleled advantages in processing a large number of clinical samples (Polson et al, 2003; Soltani & Jouyban, 2014; Souverain et al, 2004).…”

“…The pharmacokinetic study of Paxlovid in Western participants has been reported recently (Owen et al, 2021; Ravi Shankar P. Singh et al, 2022). However, there are currently no relevant reports on Chinese volunteers.…”

“…Paxlovid, a copackaged antiviral therapy for COVID‐19 consisting of nirmatrelvir tablets (150 mg) and ritonavir tablets (100 mg), was developed by Pfizer, and its emergency admission use had been issued by the Food and Drug Administration (FDA) for the treatment of adults and children with mild to moderate COVID‐19 (≥12 years old, ≥40 kg) patients (FDA, 2022; Lamb, 2022; Mahase, 2021). The activity of nirmatrelvir had been widely validated in preclinical and phase I clinical trials, and Pfizer announced that the use of Paxlovid would significantly lower hospitalization and mortality in patients with mild or moderate COVID‐19 (Ahmad et al, 2021; Eng et al, 2022; Mahase, 2021; Owen et al, 2021; Ravi Shankar P. Singh et al, 2022; Ullrich et al, 2022; Wen et al, 2022).…”

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

“…In general, by day 28, no casualties were informed among patients receiving nirmatrelvir, while 10 (1.6%) in the placebo group lost their lives (Figure 5) [25,30,47,48]. In another study, high confidence was obtained in the selection of the 300 mg nirmatrelvir diet in combination with the 100 mg ritonavir as BID over a 5-day term for phase 2/3 clinical trials in patients with COVID-19 [49]. Older people are at higher risk for severe complications from COVID-19.…”