Innovative Randomized Phase 1 Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir
R. S. P. Singh, S. S. Toussi, F. Hackman, P. L. Chan, R. Rao, R. Allen, L. Van Eyck, S. Pawlak, E. P. Kadar, F. Clark, H. Shi, A. S. Anderson, M. Binks, S. Menon, G. Nucci, A. Bergman,
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
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