Direct-acting antivirals (DAAs) have long been considered a gold-standard treatment for HCV, and lately, for COVID-19.

However, drug interactions involving ritonavir-boosted nirmatrelvir (Paxlovid) have been of particular concern; certain patients shouldn’t take the treatment if they are on specific medications.

 

Drug interactions with ritonavir

DAAs made their mark in 2011 with their high efficacy in treating HCV, as they are known to increase the viral clearance rate from 40%–50% with more than 95% when used in combination with peginterferon plus ribavirin.

Steiner S, Raguž-Lučić N, Erceg D. Direct-acting antivirals (daas): Drug-drug interactions (ddis) in the treatment of hepatitis C virus (HCV). Update on Hepatitis C. October 4, 2017.

 

The use of ritonavir-boosted nirmatrelvir to treat patients with COVID-19 has become a popular topic in the media. Direct-acting small-molecule SARS-CoV-2 antivirals target the conserved viral main protease or the conserved viral RNA-dependent RNA polymerase and not the variable spike-protein of COVID-19 virions.

Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022;198:105252.

 

This DAA combines nirmatrelvir, which is an irreversible inhibitor of the main protease of SARS-CoV-2, with the protease inhibitor ritonavir. If this treatment is started during the first days after the onset of symptoms, it has been shown to offer up to 90% protection against severe COVID-19.

Ritonavir-boosted nirmatrelvir is the only highly effective oral antiviral in the treatment of COVID-19. Ritonavir, however, is a strong cytochrome P450 3A4 inhibitor and P-glycoprotein inhibitor, according to the NIH.

Drug-drug interactions between ritonavir-boosted nirmatrelvir (Paxlovid) and concomitant medications. NIH COVID-19 Treatment Guidelines. Updated September 26, 2022.

 

However, ritonavir-boosted nirmatrelvir can interact with other drugs to possibly cause serious or lethal drug toxicities. It should not be given with strong CYP3A4 inducers such as St. John’s wort or rifampin, which can decrease nirmatrelvir and ritonavir drug levels and lower protection against COVID-19. Following the last dose of ritonavir-boosted nirmatrelvir on day 5 of treatment, the potential for interactions decreases after 2 or 3 days after the last dosage.

“The ritonavir component boosts plasma concentrations of nirmatrelvir through the potent and rapid inhibition of the key drug-metabolizing enzyme cytochrome P450 (CYP) 3A4,” wrote the authors an article published in Clinical Pharmacology & Therapeutics.

Marzolini C, Kuritzkes DR, Marra F, et al. Recommendations for the management of drug-drug interactions between the COVID-19 antiviral nirmatrelvir/ritonavir (Paxlovid) and comedications. Clin Pharmacol Ther. 2022;10.1002/cpt.2646.

“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.

 

Safe prescribing

Due to the critical nature of ritonavir-boosted nirmatrelvir in deterring severe COVID-19 infection, it’s important to recognize which drugs are contraindicated, and which can be safely co-administered.

Before prescribing ritonavir-boosted nirmatrelvir, it’s important to check for (drug-drug interactions) DDIs, including those with OTC medications, herbal supplements, or recreational drugs. The following online resources are recommended by the NIH:

• Liverpool COVID-19 Drug Interactions

• Ontario COVID-19 Science Advisory Table

• FDA Emergency Use Authorization fact sheet and checklist for ritonavir-boosted nirmatrelvir

Regarding ritonavir-boosted nirmatrelvir administration, the NIH provides useful tables broken down into four categories of DDI. These include:

• When another COVID-19 therapy should be prescribed

• When the co-administered medication should be withheld

• When the dosage of the co-administered drug should be adjusted, and the patient monitored for adverse effects

• When the co-medication should be continued, and the patient should be monitored for adverse effects

These categories include different medications from broad classes, with some medications from a class safe to take with monitoring and others within a similar or same class, unsafe to take with ritonavir-boosted nirmatrelvir. For instance, with respect to cardiovascular agents, verapamil is safe, whereas amlodipine is unsafe to take with ritonavir-boosted nirmatrelvir.

 

Managing drug interactions

When dealing with a ritonavir-boosted nirmatrelvir drug interaction, it’s important to consider the magnitude and importance of the potential interaction. Potential interventions include temporarily withholding the concomitant medication, adjusting the dose of the concomitant medication, or prescribing an alternative concomitant medication.

The NIH recommended using any of these strategies for the 5-day duration of ritonavir-boosted nirmatrelvir treatment and to continue these strategies 2 to 3 days following the last dose. If the concomitant medication has a long half-life or the patient is elderly, these strategies may need to be continued for a longer duration.

Consultation with another expert such as an HIV specialist or pharmacist is advised with patients taking highly specialized drugs that can cause concentration-dependent toxicities, including certain anticonvulsant, chemotherapeutic, neuropsychiatric, immunosuppressant, anticoagulant, or antiarrhythmic agents.