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Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2022 Jul; Vol. 112 (1), pp. 101-111. Date of Electronic Publication: 2022 May 04. - Publication Year :
- 2022
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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 <superscript>pro</superscript> 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).<br /> (© 2022 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 112
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 35388471
- Full Text :
- https://doi.org/10.1002/cpt.2603