Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
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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 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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SciScore for 10.1101/2022.02.08.22270649: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources AEs are presented by the MedDRA v24.0 term. MedDRAsuggested: NoneIn the population pharmacokinetic model, logarithmically transformed plasma nirmatrelvir concentration versus time data were analyzed with NONMEM, version 7.5.0 and the FOCE method with interaction. NONMEMsuggested: (NONMEM, RRID:SCR_016986)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations of the …
SciScore for 10.1101/2022.02.08.22270649: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources AEs are presented by the MedDRA v24.0 term. MedDRAsuggested: NoneIn the population pharmacokinetic model, logarithmically transformed plasma nirmatrelvir concentration versus time data were analyzed with NONMEM, version 7.5.0 and the FOCE method with interaction. NONMEMsuggested: (NONMEM, RRID:SCR_016986)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations of the study include that only a small number of participants were enrolled to provide an initial evaluation of safety and pharmacokinetics in healthy participants. Larger trials across various patient populations were needed to confirm nirmatrelvir/ritonavir safety and evaluate efficacy. Such large studies in patients with COVID-19 (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients [EPIC-HR], in Standard Risk Patients [EPIC-SR], and Post-Exposure Prophylaxis [EPIC-PEP]) along with clinical pharmacology studies (eg, in participants with renal or hepatic impairment), are either completed or ongoing. Study participants were also of limited ethnic diversity. However, a small number of Japanese participants were included, and no meaningful differences in safety and pharmacokinetic results were identified between Japanese and non-Japanese participants. In conclusion, in response to the urgent need for COVID-19 treatments, our innovative, seamless, and efficient approach in this study enabled accelerated dose and regimen selection for use in late phase clinical studies within 6 weeks from the first dose in humans without compromising the quality of safety and pharmacokinetic assessment, while providing the appropriate confidence to initiate pivotal efficacy trials. Nirmatrelvir/ritonavir was safe and well tolerated in healthy participants. Ritonavir enhanced nirmatrelvir pharmacokinetics, hereby expected to achieve plasma concentrations and maintain C...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04756531 Completed STUDY OF PF-07321332 IN HEALTHY PARTICIPANTS NCT04909853 Completed Renal Impairment Study of PF-07321332 Boosted With Ritonavir… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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