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

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).

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™

“…Clinical pathology findings lacked microscopic correlates, recovered completely at the end of the respective recovery phases in affected animals evaluated and were not observed in clinical studies. 26 , 27 No nirmatrelvir-related organ weight, macroscopic, or microscopic effects occurred.…”

“…Furthermore, no effects on ECG parameters were observed in the human Phase 1 studies up to projected supratherapeutic exposures. 27 The lack of any QTc prolongation in monkeys is consistent with the lack of activity in the human Ether-à-go-go-Related Gene (hERG) patch clamp assay (IC 50 >300 μM) 2 and helps support the principle of a nonclinical “double negative” (ie, low risk for hERG block and in vivo QTc prolongation) as discussed by Vargas et al 35 and described in the recent draft S7B/E14 Q&A document 36 used to inform regulatory decisions on conduct of clinical thorough QT/QTc (TQT) studies.…”

In Silico Evaluation of Paxlovid’s Pharmacometrics for SARS-CoV-2: A Multiscale Approach

“…Second, in order to reproduce the characteristic local concentration curves observed in clinical data (we refer to Figure 2A in [ 20 ]), we apply a standard pharmacokinetic (PK) dual compartment approach—akin to that utilized in [ 21 ]—assessing antiviral therapy targeting SARS-CoV-2. The latter model consists of a central compartment (e.g., stomach) responsible for first-level drug metabolism and a peripheral one (for the purpose of this manuscript the lung) containing the target site of nirmatrelvir.…”

“… Drug removal rates: . As we do not have direct information on the coefficients, we deduce them indirectly by using frequently measured nirmatrelvir blood concentration values communicated in [ 20 ]. Of course, this argument raises the question of whether it is reasonable to use blood concentration values to estimate local drug concentrations in the lung—the validity of this approach is reassured by the results of [ 22 ].…”

“…The and coefficients were set using Wolfram Mathematica [ 23 ]. We note that in the process, we also benefited from a priori information on ritonavir from [ 20 , 24 ]: we used that in non-ritonavir-boosted cases, the active component is apparently metabolized 3–4 times faster. The Wolfram Mathematica notebook is available in our public Github repository [ 25 ].…”