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

Ravi Shankar P Singh, Sima S Toussi, Frances Hackman, Phylinda L Chan, Rohit Rao, Richard Allen, Lien Van Eyck, Sylvester Pawlak, Eugene P Kadar, Frances Clark, Haihong Shi, Annaliesa S Anderson, Michael Binks, Sandeep Menon, Gianluca Nucci, Arthur Bergman, Ravi Shankar P Singh, Sima S Toussi, Frances Hackman, Phylinda L Chan, Rohit Rao, Richard Allen, Lien Van Eyck, Sylvester Pawlak, Eugene P Kadar, Frances Clark, Haihong Shi, Annaliesa S Anderson, Michael Binks, Sandeep Menon, Gianluca Nucci, Arthur Bergman

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) Mpro 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).

Conflict of interest statement

All authors are employees of Pfizer Inc. and may hold stock or stock options.

© 2022 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Study design, treatments and numbers of participants treated in Single‐ascending dose part (a) Multiple‐ascending dose part (b) and Supratherapeutic exposure part (c) of first‐in‐human study. *One participant in the nirmatrelvir 500 mg group during the single‐ascending dose part withdrew due to an adverse event. †One participant in the placebo/ritonavir group during the multiple‐ascending dose part discontinued due to participant withdrawal. In this study, which was conducted at the Pfizer Clinical Research Unit, nirmatrelvir was given as an oral suspension. Unless otherwise stated, nirmatrelvir was given under fasting conditions. During the single‐ascending dose and supratherapeutic exposure parts, participants remained in the clinical research unit during the washout. r = ritonavir.
Figure 2
Figure 2
Median plasma nirmatrelvir concentration‐time profiles (semi‐log scales) for single‐ascending dose and supratherapeutic exposure cohorts (a) and multiple‐ascending dose cohort (b). For summary statistics, values below the lower limit of quantification (10 ng/mL) were set to zero. In the supratherapeutic exposure assessment, nirmatrelvir was administered as 3 × 750 mg doses at 0, 2, and 4 hours. In the single‐ascending dose assessments where applicable and supratherapeutic exposure assessments, ritonavir 100 mg was dosed at −12 hours, 0 hours, and 12 hours after dosing. In the multiple‐ascending dose assessment, ritonavir 100 mg was dosed twice daily. The red dotted line is EC90 of 292 ng/mL (accounted for plasma protein binding). b.i.d., twice daily; EC90, concentration at which 90% inhibition of viral replication is observed.
Figure 3
Figure 3
Distribution of simulated Cmin at steady‐state with different doses (b.i.d.) enhanced with ritonavir (a), and simulation of a virtual population (n = 502) to predict viral load effect for nirmatrelvir/ritonavir 300/100 mg twice daily in symptomatic patients with COVID‐19 (b). In panel a, red dots indicate the means, grey lines indicate the medians, boxes are 25th and 75th percentiles, error bars show 10th and 90th percentiles, and the red dotted line is EC90 of 292 ng/mL (accounted for plasma protein binding). COVID‐19, coronavirus disease 2019; EC90, concentration at which 90% inhibition of viral replication is observed; PI, prediction interval; RNA, ribonucleic acid.

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