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Open Access 04-01-2024 | Ritonavir | Review Article

A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir

Authors: Jacqueline Gerhart, Donna S. Cox, Ravi Shankar P. Singh, Phylinda L. S. Chan, Rohit Rao, Richard Allen, Haihong Shi, Joanna C. Masters, Bharat Damle

Published in: Clinical Pharmacokinetics | Issue 1/2024

Abstract

Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC₉₀), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir’s cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly. Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics. When coadministered with ritonavir in patients with mild-to-moderate COVID-19, nirmatrelvir reaches a maximum concentration of 3.43 µg/mL (11.7× EC₉₀) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC₉₀). Drug interactions with nirmatrelvir/ritonavir (PAXLOVID^TM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, and to a lesser extent CYP2D6 and P-glycoprotein inhibition. Population pharmacokinetics and quantitative systems pharmacology modeling support twice daily dosing of 300 mg/100 mg nirmatrelvir/ritonavir for 5 days, with a reduced 150 mg/100 mg dose for patients with moderate renal impairment. Rapid clinical development of nirmatrelvir/ritonavir in response to the emerging COVID-19 pandemic was enabled by innovations in clinical pharmacology research, including an adaptive phase 1 trial design allowing direct to pivotal phase 3 development, fluorine nuclear magnetic resonance spectroscopy to delineate absorption, distribution, metabolism, and excretion profiles, and innovative applications of model-informed drug development to accelerate development.

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Title: A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir
Authors: Jacqueline Gerhart
Donna S. Cox
Ravi Shankar P. Singh
Phylinda L. S. Chan
Rohit Rao
Richard Allen
Haihong Shi
Joanna C. Masters
Bharat Damle
Publication date: 04-01-2024
Publisher: Springer International Publishing
Keywords: Ritonavir
SARS-CoV-2
Pharmacokinetics
COVID-19
Published in: Clinical Pharmacokinetics / Issue 1/2024
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-023-01339-y

At a glance: The STEP trials

Springer Medicine

A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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