Abstract
Coronavirus disease 2019 (COVID-19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) M pro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. 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 I study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a three-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). 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 II/III trials (300/100 mg b.i.d.), 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 which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials’ initiation ( NCT04756531 ).
【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, Coronavirus disease 2019, clinical trial, Trial, Safety, Antiviral, Hospitalization, Phase I, Ritonavir, in vitro, antiviral activity, Severe acute respiratory syndrome, Randomized, Cohort, Viral load, viral replication, modeling, death, Placebo, PF-07321332, inhibitor, Quantitative, placebo-controlled, safety profile, Nirmatrelvir, half-life, pharmacokinetic, Clinical efficacy, Concentration, dose, severe disease, Safe, double-blind, regimen, Tolerability, M pro, cohorts, Coronaviridae family, pharmacokinetic data, SARS-CoV-2-infected patients, enhancer, FIVE, Prevent, decrease, significantly, evaluated, required, supported, demonstrated, suggested, accelerated, MAD, SARS-CoV-2-infected patient, seamless, 【제목키워드】 COVID-19, Selection, Dosing, phase,