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

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 t...

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Autores principales: Singh, Ravi Shankar P., Toussi, Sima S., Hackman, Frances, Chan, Phylinda L., Rao, Rohit, Allen, Richard, Van Eyck, Lien, Pawlak, Sylvester, Kadar, Eugene P., Clark, Frances, Shi, Haihong, Anderson, Annaliesa S., Binks, Michael, Menon, Sandeep, Nucci, Gianluca, Bergman, Arthur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087011/
https://www.ncbi.nlm.nih.gov/pubmed/35388471
http://dx.doi.org/10.1002/cpt.2603
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author Singh, Ravi Shankar P.
Toussi, Sima S.
Hackman, Frances
Chan, Phylinda L.
Rao, Rohit
Allen, Richard
Van Eyck, Lien
Pawlak, Sylvester
Kadar, Eugene P.
Clark, Frances
Shi, Haihong
Anderson, Annaliesa S.
Binks, Michael
Menon, Sandeep
Nucci, Gianluca
Bergman, Arthur
author_facet Singh, Ravi Shankar P.
Toussi, Sima S.
Hackman, Frances
Chan, Phylinda L.
Rao, Rohit
Allen, Richard
Van Eyck, Lien
Pawlak, Sylvester
Kadar, Eugene P.
Clark, Frances
Shi, Haihong
Anderson, Annaliesa S.
Binks, Michael
Menon, Sandeep
Nucci, Gianluca
Bergman, Arthur
author_sort Singh, Ravi Shankar P.
collection PubMed
description 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).
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spelling pubmed-90870112022-05-10 Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir Singh, Ravi Shankar P. Toussi, Sima S. Hackman, Frances Chan, Phylinda L. Rao, Rohit Allen, Richard Van Eyck, Lien Pawlak, Sylvester Kadar, Eugene P. Clark, Frances Shi, Haihong Anderson, Annaliesa S. Binks, Michael Menon, Sandeep Nucci, Gianluca Bergman, Arthur Clin Pharmacol Ther Research 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). John Wiley and Sons Inc. 2022-05-04 2022-07 /pmc/articles/PMC9087011/ /pubmed/35388471 http://dx.doi.org/10.1002/cpt.2603 Text en © 2022 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research
Singh, Ravi Shankar P.
Toussi, Sima S.
Hackman, Frances
Chan, Phylinda L.
Rao, Rohit
Allen, Richard
Van Eyck, Lien
Pawlak, Sylvester
Kadar, Eugene P.
Clark, Frances
Shi, Haihong
Anderson, Annaliesa S.
Binks, Michael
Menon, Sandeep
Nucci, Gianluca
Bergman, Arthur
Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
title Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
title_full Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
title_fullStr Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
title_full_unstemmed Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
title_short Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
title_sort innovative randomized phase i study and dosing regimen selection to accelerate and inform pivotal covid‐19 trial of nirmatrelvir
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087011/
https://www.ncbi.nlm.nih.gov/pubmed/35388471
http://dx.doi.org/10.1002/cpt.2603
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