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

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.

Physiologically‐Based Pharmacokinetic Modeling‐Guided Dose Management of Oral Anticoagulants when Initiating Nirmatrelvir/Ritonavir (Paxlovid) for COVID‐19 Treatment

“…Considering the enzyme half‐lives of 20–30 hours for CYP3A4 and CYP2J2 and simulated recoveries of CYP3A4 (liver), CYP3A4 (gut), and CYP2J2 activities post‐MBI by ritonavir were 62.4%, 82.1%, and 77.6%, respectively, the reduced dose of rivaroxaban could be maintained for 3 days post‐nirmatrelvir/ritonavir treatment, which was in accordance with recommendations by Marzolini et al . 9 and Hong et al . 25 …”

“…1 , 2 However, direct clinical data between nirmatrelvir/ritonavir and oral anticoagulants are still limited. 8 , 9 Notably, application of PBPK models in diseased and specific populations, in addition to DDIs, has demonstrated promising performance in the evaluation of clinically relevant yet untested scenarios. 23 PBPK‐guided dose recommendations, as an alternative to real‐world studies, have been approved in several drug labels in recent years, 23 , 24 and has been applied for nirmatrelvir/ritonavir‐related study.…”

The feasibility, safety, and efficacy of Paxlovid treatment in SARS-CoV-2-infected children aged 6–14 years: a cohort study

“…Compared with placebo, early initiation of Paxlvoid can significantly reduce the risk of hospitalization or death in mild-to-moderate cases compared with placebo (7). On 22 December 2021, Paxlovid received emergency use authorization in the United States for the treatment of mild-to-moderate COVID-19 infection in adults and children (≥12 years, weighing ≥40 kg) who are at risk of progressing to a severe form of infection (17). Similarly, in the updated edition of the COVID-19 drug treatment guidelines by the World Health Organization (WHO) on 22 April 2022, Paxlovid is recommended for patients with suitable indications (18), to prevent the disease progression as soon as possible by early implementation of antiviral therapy to inhibit viral replication.…”

Assessing the proportion of the Danish population at risk of clinically significant drug-drug interactions with new oral antivirals for early treatment of COVID-19

“…Ritonavir is a strong inhibitor of cytochrome P450 (CYP) 3A4 inhibitor and P-glycoprotein. Therefore, NMV/r has a high potential for significant drug-drug interactions (DDI) ( Marzolini et al, 2022 ). No clinically significant DDIs have yet been identified with molnupiravir ( European Medicines Agency, 2022 ).…”

“…Many DDIs can be managed by dose adjustments or temporarily withholding one or more drugs ( Marzolini et al, 2022 ). Recovery of CYP3A activity after discontinuation of NMV/r may take 2-5 days, and paused medicine should not be resumed until 3 days after ( Stader et al, 2020 ).…”