Ritonavir-boosted Nirmatrelvir (Paxlovid)
Overview and Development
Paxlovid is a combination of the drugs nirmatrelvir and ritonavir.[3] Nirmatrelvir (formerly PF-07321332) is a novel SARS-CoV-2 peptidomimetic protease inhibitor active against Mpro. Mpro is a protease that contributes to viral replication by cleaving viral polyproteins. It may also be referred to as a 3CLpro or nsp5 protease inhibitor.[3] Ritonavir has been utilized for decades as a protease inhibitor for the treatment of HIV.[4] While ritonavir does not have activity against SARS-CoV-2, it is a strong CYP3A inhibitor that increases nirmatrelvir concentrations.[3] The dosing of N-R is 300 mg of nirmatrelvir (two 150-mg tablets) with 100 mg (one 100-mg tablet) of ritonavir orally twice daily for 5 days. Patients should begin taking this medication as soon as possible after their diagnosis of COVID-19 and within 5 days of symptom onset.[3]
Dosing Adjustments
The dosing of N-R should be adjusted in renal dysfunction. In an open-label study evaluating its pharmacokinetics, the area under the curve of nirmatrelvir was increased by 87% in moderate renal impairment and 204% in severe renal impairment.[3] For an eGFR of 30 to <60, the dosage should be reduced to 150 mg of nirmatrelvir with 100 mg of ritonavir taken twice daily. The packaging for N-R is unique, as it contains five blister packs, one for each day. For patients who require a dosage adjustment for renal function, pharmacists are required to remove the extra nirmatrelvir tablets and place a preprinted sticker over the empty blister areas. The Institute for Safe Medication Practices provides a detailed explanation of these instructions.[5] In severe renal impairment with an eGFR <30, this medication is not recommended.[3]
No dosage adjustment is required for mild-to-moderate hepatic impairment. It is not recommended in severe hepatic impairment with Child-Pugh Class C.[3]
N-R received EUA from the FDA on December 22, 2021. It is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years or older and weighing a minimum of 40 kg.
Efficacy
The primary clinical trial of N-R is the Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) trial.[3,6] In this phase II/III multinational, double-blind trial, nonhospitalized symptomatic adults (N = 2,246) with a positive test for SARS-CoV-2 were randomized to receive N-R or placebo for 5 consecutive days. Patients were enrolled within 5 days of the onset of their symptoms and had a minimum of one COVID-19 sign or symptom on the day of randomization.[6] To be included, they were required to have a minimum of one risk factor or characteristic for progression to severe disease. Patients were excluded if they had active liver disease, had moderate-to-severe renal impairment, were pregnant/breastfeeding, had known HIV with a viral load >400 copies/mL, or were taking medications such as ritonavir for HIV. Importantly, patients were also excluded if they were receiving medications that relied on CYP3A4 for clearance or medications that were strong CYP3A inducers. These patients had not received a vaccine for COVID-19 nor had a prior infection of COVID-19.[6] Patients were permitted to receive the standard of care, including monoclonal antibodies, though the primary endpoint was only evaluated in those who did not receive a monoclonal antibody.
The primary endpoint in this study was hospitalization related to COVID-19 or death from any cause at 28 days.[6] The average age was 46 years, and 51% of patients were men. The primary endpoint occurred in eight patients in the N-R group (0.77%) versus 66 patients in the placebo group (6.3%), which is an 88% relative risk reduction (P <.001). There were zero deaths in the N-R group and 12 in the placebo group. Adverse effects occurred in fewer than 10% of patients in each group. Adverse effects more common in the N-R group included dysgeusia and diarrhea.[6]
Interim data are also available for the Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR) phase II/III trial.[7,8] In this study, unvaccinated adults at standard risk and vaccinated adults with one or more risk factors for progressing to severe disease were randomized to receive N-R or placebo. This study had a unique primary outcome of self-reported resolution of symptoms for 4 consecutive days. Interim analysis demonstrated a nonsignificant relative risk reduction of 51%, and the study has ceased enrollment.[7,8] N-R is also being evaluated for postexposure prophylaxis in the Epic PEP trial (currently ongoing).[9]
Clinical Application
N-R received EUA from the FDA on December 22, 2021.[3] It is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years or older and weighing a minimum of 40 kg. Per the EUA, patients should have positive results of a SARS-CoV-2 viral test and be at high risk for progression to severe COVID-19, with potential for hospitalization or death.[3] The CDC provides a list of underlying medical conditions associated with higher risk of severe COVID-19. These include cancer, cardiovascular disease, cerebrovascular disease, chronic kidney or liver disease, chronic lung conditions, diabetes, mental health disorders, obesity, smoking, and others.[10] N-R demonstrates activity against all known human coronaviruses, including mutations such as the Omicron variant, though limited data are available.[2,11] There are limitations to the EUA for this medication. This therapy is not authorized for initiation in the hospital setting, use as prophylaxis, or use for more than a 5-day duration.[3] If a patient begins N-R as an outpatient and is then hospitalized, the 5-day course may be completed in the hospital setting.[2]
Per the National Institutes of Health (NIH) COVID-19 Treatment Guidelines, N-R is preferred (as an AIIa-level recommendation) over other outpatient treatment recommendations of remdesivir (BIIa), bebtelovimab (CIII), or molnupiravir (CIIa).[2] However, there are no direct comparisons of efficacy or safety for these agents. Data are not available for combinations of these therapies.[2] The Infectious Diseases Society of America suggests N-R within 5 days of symptom onset for outpatients with mild-to-moderate COVID-19 at high risk for progression to severe disease.[12] The World Health Organization (WHO) recommends administering N-R in patients with nonsevere illness who are at the highest risk of hospitalization with a conditional recommendation against it in those who are at low risk for hospitalization.[13]
Special Populations
Though there are no human data for patients who are pregnant or breastfeeding, the NIH panel recommends N-R for pregnant patients as the benefits likely outweigh the risks.[2] Additionally, the Society for Maternal-Fetal Medicine issued a statement supporting the use of N-R for the treatment of pregnant patients who meet clinical criteria. They state that it should not be withheld due to pregnancy or lactation.[14] Though the EPIC-HR trial excluded pediatric patients, N-R received its EUA for pediatric patients aged 12 years or older and who weigh a minimum of 40 kg.[3] The adult dose is expected to reach similar concentrations in these adolescent patients.[3]
Drug Interactions
Pharmacists have a significant role in evaluating a patient's medications for interactions with N-R. N-R is contraindicated with medications that are highly dependent on CYP3A for clearance or those that are strong inducers and could significantly reduce the concentrations of nirmatrelvir or ritonavir.[3] The NIH recommends providers consult with a pharmacist or HIV specialist regarding the drug interactions with N-R.[15] They also recommend obtaining a complete list of the patient's medications, including those that are herbal and OTC. Strategies to facilitate the use of N-R include dose adjustment of the interacting medication (the dose of N-R should not be adjusted), use of an alternative of the interacting medication, increased monitoring, and/or temporarily holding the interacting medication.[15] These strategies should be implemented for the 5-day course of N-R and for 3 to 5 days after completion of treatment.[15] Patients should be informed of any of these drug interactions and if N-R can be safely used. A list of commonly prescribed medications and management strategies with N-R is provided (see Table 1), although this table is not comprehensive.[15] Online databases and applications can be utilized to evaluate for drug-drug interactions, and the NIH guidelines recommend the use of the website https://www.covid19-druginteractions.org/ as a resource.[15]
The MOVe-OUT trial evaluated molnupiravir in outpatients with COVID-19. Hospitalization or death by Day 29 occurred in 6.8% of patients who received molnupiravir versus 9.7% of patients in the placebo group.
US Pharmacist. 2022;47(7):34-41. © 2022 Jobson Publishing
