Patients with advanced chronic kidney disease (CKD) have increased risks for hospitalization and death after COVID-19 infection. Yet PaxlovidTM (nirmatrelvir and ritonavir), the preferred antiviral agent to mitigate those risks at symptom onset, is not currently indicated for patients with stage 4 or 5 CKD. An editorial published in the Clinical Journal of the American Society of Nephrology suggests use of low-dose Paxlovid regimens may be feasible in advanced CKD.
According to the FDA’s Paxlovid emergency use authorization (EAU), the standard dose is 300 mg nirmatrelvir (two 150 mg tablets) and 100 mg ritonavir (one 100 mg tablet) with all 3 oral tablets taken twice daily for 5 days after symptom onset. In an FDA Q&A article, John Farley, MD, MPH, director of the Office of Infectious Diseases in the Center for Drug Evaluation and Research’s Office of New Drugs stated that standard dosing can be used in patients with an estimated glomerular filtration rate (eGFR) of 60 to 90 mL/min/1.73 m2. Patients with moderate CKD (eGFR 30 to 60 mL/min/1.73 m2), however, should receive a reduced dosage of 150 mg nirmatrelvir (one 150 mg tablet) and 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days. The EAU currently does not recommended Paxlovid in patients with severe CKD (eGFR less than 30 mL/min/1.73 m2) because nirmatrelvir, which is partly excreted by the kidney, may accumulate with decreasing kidney function.
Reduced Dosing Proposed
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Swapnil Hiremath, MD, MPH, of the University of Ottawa in Canada and colleagues conducted an unpublished case series of 15 patients on dialysis who were treated with a modified reduced-dose regimen of nirmatrelvir/ritonavir. The investigators found that a single dose of nirmatrelvir has some antiviral activity in patients with an eGFR less than 30 mL/min/1.73 m2, and its hemodialysis clearance is clinically insignificant. Dr Hiremath coauthored the recent editorial.
“A dose of 300 mg nirmatrelvir (with 100 mg ritonavir) on day 1, followed by 150 mg nirmatrelvir (with 100 mg ritonavir) administered daily, given after hemodialysis on dialysis days, should provide effective blood concentrations for enzyme inhibition,” the editorialists suggested.
In an interview with Renal & Urology News, Robert Grossberg, MD, medical director of the Center for Positive Living/Infectious Diseases Clinic at Montefiore Health System and an associate professor at Albert Einstein College of Medicine in the Bronx, New York, who was not involved in the study or editorial, commented:
“From what we know about the pharmacology of ritonavir and nirmatrelvir, we can expect a modified strategy with lower doses would achieve effective drug levels and work just as well. This strategy appears safe, particularly since the drugs are given for only 5 days.”
Dr Grossberg said he would consider a reduced-dose Paxlovid strategy to treat a patient with CKD stage 4-5 or on hemodialysis.
Potential Drug Interactions
Ritonavir is a potent CYP3A4 inhibitor and an inducer of other cytochrome p450 enzymes. Statins, calcineurin inhibitors, hormonal contraceptives containing ethinyl estradiol, and medications for HIV-1 treatment are among the long list of medications that may interact with Paxlovid according to the National Institutes of Health. Drugs commonly prescribed to patients with CKD such as statins, calcium channel blockers, and direct-acting oral anticoagulants may need to be temporarily suspended to reduce the chances of drug interactions. The FDA has provided a Fact Sheet for Health Care Providers and a Prescriber Patient Eligibility Screening Checklist to aid decision making.
Infectious disease specialist Rachel M. Bartash, MD, also at Montefiore and an assistant professor at Albert Einstein College of Medicine, said providers need to be aware of the many potential drug-drug interactions before prescribing the antiviral medication.
Kidney Transplant Recipients
In kidney transplant patients, Paxlovid can lead to significant elevation in levels of calcineurin inhibitors, resulting in toxicity, Dr Bartash said. Ritonavir may also affect levels of mycophenolic acid and sirolimus.
“The use of Paxlovid in kidney transplant recipients is challenging and requires modification of immunosuppressive regimens and close monitoring of drug levels,” Dr Bartash said. Given these challenges and the availability of other safe and effective treatments, we typically avoid the use of Paxlovid in this population.”
Dr Hiremath and his fellow editorialists noted that the American Society of Transplantation has provided guidance on use of nirmatrelvir/ritonavir in kidney transplant recipients with an eGFR greater than 30 mL/min/1.73 m2. Use in recipients with an eGFR less than 30 mL/min/1.73 m2 “should be considered cautiously in consultation with experienced teams, including infectious disease and pharmacy,” they wrote. Consultations are also required for patients with CKD due to glomerulonephritis who are taking immunosuppressive drugs.
Adverse Effects
Ritonavir is hepatotoxic and should not be used in patients with liver abnormalities, infections, or diseases. In the original trial, dysgeusia, diarrhea, hypertension, and myalgia were commonly reported.
Rebound After Paxlovid Treatment
A CDC advisory confirmed in May 2022 that some individuals who take Paxlovid experience a return of symptoms 2-8 days after finishing the 5-day treatment and testing negative for COVID-19.
“There is no data to support giving a second course of Paxlovid or other treatment,” Dr Grossberg said, “but in patients with severe symptoms or immunocompromising conditions, it might be worth considering.”
Alternative COVID-19 Treatments
Dr Grossberg and Dr Bartash both pointed out that alternative COVID-19 treatments exist for patients with CKD instead of Paxlovid. The oral drug molnupiravir is not adjusted for kidney function and shows some effectiveness (although less so than Paxlovid) in preventing progression to serious illness and hospitalization. Other options include monoclonal antibodies and high-titer convalescent plasma, both of which are safe in patients with CKD and kidney transplant recipients.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
References
Pfizer. PaxlovidTM [package insert]. U.S. Food and Drug Administration website. Fact sheet for healthcare providers: Emergency use authorization for PaxlovidTM. Accessed on July 5, 2022 at https://www.fda.gov/media/155050/download
Hiremath S, McGuinty M, Argyropoulos C, et al. Prescribing nirmatrelvir/ritonavir (Paxlovid) for COVID-19 in advanced chronic kidney disease. Clin J Am Soc Nephrol. Publishing June 9, 2022. doi:10.2215/CJN.05270522
Antoine Brown P, McGuinty M, Argyropoulos C. Early experience with modified dose nirmatrelvir/ritonavir in dialysis patients with coronavirus disease-2019. MedRxiv website. Updated May 21, 2022. Accessed July 8, 2022 at https://www.medrxiv.org/content/10.1101/2022.05.18.22275234v1.article-info
FDA updates on Paxlovid for health care providers. US Food and Drug Administration website. Updated May 4, 2022. Accessed July 8, 2022 at https://www.fda.gov/drugs/news-events-human-drugs/fda-updates-paxlovid-health-care-providers
Drug-drug interactions between ritonavir-boosted nirmatrelvir (Paxlovid) and concomitant medications. National Institutes of Health. Updated May 13, 2022. Accessed July 8, 2022 at https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir–paxlovid-/paxlovid-drug-drug-interactions/
COVID-19 rebound after Paxlovid treatment. Centers for Disease Control and Prevention. Updated May 24, 2022. Accessed July 8, 2022 at https://emergency.cdc.gov/han/2022/han00467.asp
Rubin R. From positive to negative to positive again—The mystery of why COVID-19 rebounds in some patients who take paxlovid. JAMA. Published online June 8, 2022. doi:10.1001/jama.2022.9925
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