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Review
. 2022 Dec;112(6):1191-1200.
doi: 10.1002/cpt.2646. Epub 2022 Jun 7.

Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications

Catia Marzolini  1   2 , Daniel R Kuritzkes  3 , Fiona Marra  2   4 , Alison Boyle  2   4 , Sara Gibbons  2 , Charles Flexner  5 , Anton Pozniak  6   7 , Marta Boffito  6 , Laura Waters  8 , David Burger  9   10 , David J Back  2 , Saye Khoo  2
Affiliations
Review

Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications

Catia Marzolini et al. Clin Pharmacol Ther. 2022 Dec.

Abstract

The coronavirus disease 2019 (COVID-19) antiviral nirmatrelvir/ritonavir (Paxlovid) has been granted authorization or approval in several countries for the treatment of patients with mild to moderate COVID-19 at high risk of progression to severe disease and with no requirement for supplemental oxygen. Nirmatrelvir/ritonavir will be primarily administered outside the hospital setting as a 5-day course oral treatment. The ritonavir component boosts plasma concentrations of nirmatrelvir through the potent and rapid inhibition of the key drug-metabolizing enzyme cytochrome P450 (CYP) 3A4. Thus nirmatrelvir/ritonavir, even given as a short treatment course, has a high potential to cause harm from drug-drug interactions (DDIs) with other drugs metabolized through this pathway. Options for mitigating risk from DDIs with nirmatrelvir/ritonavir are limited due to the clinical illness, the short window for intervention, and the related difficulty of implementing clinical monitoring or dosage adjustment of the comedication. Pragmatic options are largely confined to preemptive or symptom-driven pausing of the comedication or managing any additional risk through counseling. This review summarizes the effects of ritonavir on drug disposition (i.e., metabolizing enzymes and transporters) and discusses factors determining the likelihood of having a clinically significant DDI. Furthermore, it provides a comprehensive list of comedications likely to be used in COVID-19 patients which are categorized according to their potential DDI risk with nirmatrelvir/ritonavir. It also discusses recommendations for the management of DDIs which balance the risk of harm from DDIs with a short course of ritonavir, against unnecessary denial of nirmatrelvir/ritonavir treatment.

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Conflict of interest statement

C.M. received a research grant from Gilead and lecture honoraria from MSD and ViiV; D.R.K. has received consulting fees from Atea, Gilead, GSK, Janssen, Merck, Novartis, and ViiV, and research support from Atea, Gilead, Merck, and ViiV; F.M. has received educational grants and/or consulting fees from ViiV, Gilead, and Merck; A.B. has received educational grants and lecture honoraria from Gilead and Abbvie. S.G. has received no direct grants/research support but is an employee of the University of Liverpool and is funded by external research income sources awarded to the Liverpool Drug Interaction Group from BHIVA, EACS, Glasgow HIV Drug Therapy, NIHR, UKRI, AbbVie, Gilead, MSD, Novartis, Sobi, Thera Technologies, and ViiV; C.F. reports serving as a paid consultant for Gilead Sciences, Janssen, Merck, and ViiV Healthcare; A.P. has received research grants and/or consulting fees from ViiV, Gilead, MSD, Theratech, and Janssen; M.B. has received research grants and/or consulting fees from ViiV, Gilead, MSD, GSK, Novavax, Valneva, Cipla, Mylan, Janssen, and Roche; L.W. has received research grants and/or consulting fees from ViiV, Gilead, MSD, Theratech, Cipla, Mylan, and Janssen; D.B. is working at Radboud University Medical Center, which has received research grants from ViiV, Merck, and Gilead; D.J.B. has received educational grants from AbbVie, Novartis, Merck, Gilead, and Sobi and lecture/consultancy fees from AbbVie, Gilead, Merck, and ViiV; S.K. has received educational grants for the Liverpool drug interaction website (www.covid‐druginteractions.org) from AbbVie, Gilead, MSD, Novartis, and Sobi. S.K. has also received speakers' honoraria from ViiV Healthcare, Gilead Sciences, and AbbVie; consultancy fees from ViiV Healthcare and Merck; and research funding from Gilead Sciences and ViiV Healthcare.

Figures

Figure 1
Figure 1
Disappearance of CYP3A4 inhibition 1, 2 3, 4, and 5 days after stopping ritonavir for different age groups. The data are presented as mean value with the 95% confidence interval (adapted from ref. 11). CYP, cytochrome P450.
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