What evidence evaluates the use of Paxlovid™ (nirmatrelvir/ritonavir) in severe renal impairment?

Introduction
Paxlovid™ (nirmatrelvir/ritonavir) is an anti-SARS-CoV-2 antiviral approved by the Food and Drug Administration (FDA) in 2023 for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19.1 The efficacy of nirmatrelvir/ritonavir in the treatment of COVID-19 was established in the Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) trial.2 EPIC-HR was a randomized, double-blind, placebo-controlled clinical trial in adults who were at increased risk of developing severe illness. Unfortunately, exclusion of patients with moderate to severe renal impairment from the EPIC-HR trial prompted the manufacturer to recommend against nirmatrelvir/ritonavir use in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) although dosage adjustment recommendations are available for patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m2 to <60 mL/min/1.73 m2).1,2 A summary of FDA-approved doses is provided in Table 1.

The lack of information available for patients with severe renal impairment presents a significant therapeutic knowledge gap as many patients with severe renal impairment are at risk for severe COVID-19, and antivirals have been shown to reduce all-cause hospitalization and death in these patients.3 A review of the literature to aid clinicians in appropriate use of nirmatrelvir/ritonavir for patients with severe renal impairment is warranted.

Table 1. FDA-approved dosing for nirmatrelvir/ritonavir.1
eGFR (mL/min/1.73 m2)Recommendations
Usual dose--300 mg nirmatrelvir/100 mg ritonavir twice daily for 5 days
Mild renal impairment≥60 to <90300 mg nirmatrelvir/100 mg ritonavir twice daily for 5 days
Moderate renal impairment≥30 to <60150 mg nirmatrelvir/100 mg ritonavir twice daily for 5 days
Severe renal impairment<30Not recommended
ESRD receiving dialysis--Not recommended
Abbreviations: eGFR=estimated glomerular filtration rate; ESRD=end-stage renal disease.

Guideline recommendations
Although the National Institutes of Health no longer update their COVID-19 treatment guidelines, the final version does note that although data are limited for the use of ritonavir-boosted nirmatrelvir in patients with eGFR <30 mL/min/1.73 m2, dosing adjustments have been proposed in the literature.4 The guideline does not, however, provide additional information.

The Infectious Diseases Society of America (IDSA) now maintains COVID-19 guidelines; however, their recommendations for the use of nirmatrelvir/ritonavir in severe renal impairment mimic those of the prescribing information.5 Thus, nirmatrelvir/ritonavir is not recommended in patients with eGFR <30 mL/min/1.73 m2.

Canadian guidelines from Ontario Health updated in 2024 do include dosing recommendations for nirmatrelvir/ritonavir in patients with an eGFR <30 mL/min/1.73 m2.6 They recommend nirmatrelvir 300 mg/ritonavir 100 mg on day 1 followed by nirmatrelvir 150 mg/ritonavir 100 mg once daily on days 2 to 5. The same dose is recommended for patients who are receiving hemodialysis or peritoneal dialysis and weigh at least 40 kg. For those receiving dialysis who weigh less than 40 kg, they recommend a dose of nirmatrelvir 150 mg/ritonavir 100 mg every 48 hours for 3 doses. They recommend dosing after dialysis, on dialysis days.

Literature review
Numerous observational studies have evaluated modified doses of nirmatrelvir/ritonavir in patients with severe renal impairment and/or those receiving dialysis. Summaries of studies or case series describing clinical outcomes and enrolling at least 5 patients are summarized in Table 2.7-11

The studies in Table 2 included a heterogenous patient population including those with mild, moderate, or severe renal impairment.7-11 The current literature supporting the use of nirmatrelvir/ritonavir in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) consists primarily of retrospective cohort studies. The literature generally supports nirmatrelvir/ritonavir as safe and effective for these patients at a dose of nirmatrelvir 300 mg/ritonavir 100 mg on day 1 followed by nirmatrelvir 150 mg/ritonavir 100 mg once daily on days 2 to 5. A similar dose appears to be appropriate for dialysis patients who weigh at least 40 kg with a lower dose in lighter weight patients. The dose for moderate renal impairment in these observational studies is generally consistent with the prescribing information.

In addition to the studies included in the table, a key pharmacokinetic trial by Toussi et al (2022) found increased systemic exposure of nirmatrelvir in patients with mild (60 to <90 mL/min/1.73 m2; 124%), moderate (30 to <60 mL/min/1.73 m2; 187%), or severe (<30 mL/min/1.73 m2; 304%) renal impairment.12 The authors recommended a dose of nirmatrelvir 150 mg/ritonavir 100 mg twice daily in patients with moderate renal impairment which is consistent with prescribing information. However, the authors made no recommendations for patients with severe renal failure, noting that more study was necessary.

A 2024 study by Chu et al (not included in the table due to lack of standardized dosing) retrospectively compared outcomes of COVID-19 treatment with either molnupiravir or nirmatrelvir-ritonavir in 4,886 patients with eGFR <30 mL/min/1.73 m2.13 The study found lower all-cause mortality (5.06% vs 7.97%) and hospitalization (23.98% vs 28.14%) with nirmatrelvir-ritonavir; however, the doses of nirmatrelvir-ritonavir were not standardized, and although the study supports positive outcomes with the use of nirmatrelvir-ritonavir in patients with severe renal impairment, it does not offer guidance on appropriate dosage and administration in this patient population. Similarly, a small (N=27), single-center report retrospectively compared outcomes with molnupiravir and nirmatrelvir-ritonavir in patients with eGFR <30 mL/min/1.73 m2.14 This report found a higher adverse event incidence in those receiving nirmatrelvir-ritonavir (66.7% vs 20%), but all AEs in the molnupiravir group lead to discontinuation while fewer (16.7%) lead to discontinuation in the nirmatrelvir-ritonavir group. This report did not specify a nirmatrelvir-ritonavir dosing regimen.

There is very little information in critically patients receiving continuous renal replacement therapy (CRRT); however, one pharmacokinetic study found significantly elevated concentrations of nirmatrelvir in patients undergoing CRRT using usual doses.15 The authors were unable to suggest an appropriate dose, but recommended dosage adjustment for these patients.

Table 2. Observational studies in patients with severe renal impairment.7-11
Study design SubjectsNirmatrelvir/ritonavir regimenKey clinical outcomes
Chan et al (2023)

Prospective, single-arm		N=85 patients who were within 5 days of a COVID-19 diagnosis; 65 patients had an eGFR <30 mL/min/1.73m2 including 59 receiving dialysiseGFR >60 (controls): 300 mg nirmatrelvir/100 mg ritonavir twice daily days 1 to 5 (n=10)
eGFR 30-60 (n=10): 150 mg nirmatrelvir/100 mg ritonavir twice daily days 1 to 5 (n=10)
eGFR<30 (no dialysis): 300 mg nirmatrelvir/100 mg ritonavir day 1 and 150 mg nirmatrelvir/100 mg ritonavir once daily days 2 to 5 (n=6)
Dialysisa (n=59)
≥40 kg: 300 mg nirmatrelvir/100 mg ritonavir on day 1 followed by 150 mg nirmatrelvir/100 mg ritonavir once daily on days 2 to 5
<40 kg: 150 mg nirmatrelvir/100 mg ritonavir on day 1 followed by 150 mg nirmatrelvir/100 mg ritonavir every 48 hours		AE incidence similar between low (<30 mL/min/1.73 m2) GFR (9.2%) and high (≥30 mL/min/1.73 m2) GFR (10%)

Serious AE incidence was also similar between high and low GFR groups (5% and 6.2%, respectively)

Time to COVID-19 resolution was similar between groups (19.4 days vs 17.9 days)
Hiremath et al (2023)

Retrospective cohort		N=134 patients receiving dialysis who were within 5 days of a COVID-19 diagnosis (88% HD/12% PD)300 mg nirmatrelvir/100 mg ritonavir on day 1 followed by 150 mg nirmatrelvir/100 mg ritonavir on days 2 to 596% of patients completed the treatment

6% of patients had a COVID-19 related hospitalization but no deaths related to COVID-19 were reported in 30 days of follow-up
Lafont et al (2024)

Retrospective cohort		N=13 patients with an eGFR <30 mL/min/1.73m2 (2 patients receiving dialysis) and mild COVID-19300 mg nirmatrelvir/100 mg ritonavir on day 1 followed by 150 mg nirmatrelvir/100 mg ritonavir on days 2 to 5No major AEs

All patients alive and asymptomatic at day 28
Yan et al (2023)

Retrospective cohort		N=195 patients with impaired renal function and COVID-19 infection; 73 received antiviraleGFR 30 to <60: 150 mg nirmatrelvir/100 mg ritonavir twice daily days 1 to 5 (n=93; 45 received antiviral)
eGFR <30 (no dialysis): 150 mg nirmatrelvir/100 mg ritonavir once daily days 1 to 5 (n=40; 9 received antiviral)
HDa: 150 mg nirmatrelvir/100 mg ritonavir once daily days 1 to 5 (n=62; 19 received antiviral) 		Composite of all-cause mortality, ICU admission, or CV events was lower in patients who received nirmatrelvir/ritonavir vs controls (27.4% vs 46.7%; p=0.008)

Duration of viral shedding was shorter among those treated with nirmatrelvir/ritonavir (5 days vs 13 days; p<0.001)

Length of hospital stay was also shorter in the treated patients (16 days vs 17.5 days; p=0.026)
Yang et al (2024)

Retrospective cohort		N=40 kidney transplant patients with eGFR <30 mL/min/1.73m2 with moderate to severe COVID-19300 mg nirmatrelvir/100 mg ritonavir twice daily (n=8)

150 mg nirmatrelvir/100 mg ritonavir twice daily (n=15)

300 mg nirmatrelvir/100 mg ritonavir once daily (n=9)

150 mg nirmatrelvir/100 mg ritonavir once daily (n=8)		No patients experienced disease progression but 2 patients with baseline severe COVID-19 (and delayed start of treatment) died by day 28

There were no severe AEs but 2 cases of hypertension and 1 case each of hyperglycemia, decreased albumin, abnormal liver function, and stomach discomfort occurred

Higher doses were associated with more AEs with 2 AEs in the highest dose group and no AEs in the lowest dose group
Abbreviations: AE=adverse events CV=cardiovascular; eGFR=estimated glomerular filtration rate; GFR=glomerular filtration rate; HD=hemodialysis; ICU=intensive care unit; PD=peritoneal dialysis.
aGiven after dialysis in HD patients.

Conclusion
Although the evidence is limited to small and primarily observational trials, dose-adjusted nirmatrelvir/ritonavir appears to be appropriate for patients with COVID-19 who have moderate or severe renal impairment as well as those patients undergoing dialysis. Careful adverse event and drug interaction monitoring is warranted.

References

  1. Paxlovid. Package insert. Pfizer; 2024.
  2. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542
  3. Chen CC, Huang CY, Wu JY, et al. Clinical effectiveness of oral antiviral agents for treating non-hospitalized COVID-19 patients with chronic kidney disease. Expert Rev Anti Infect Ther. 2024;22(8):705-712. doi:10.1080/14787210.2024.2334052
  4. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Updated March 1, 2024. Accessed February 10, 2025. https://www.ncbi.nlm.nih.gov/books/NBK570371/pdf/Bookshelf_NBK570371.pdf
  5. IDSA Guidelines on the Treatment and Management of Patients with COVID-19. Infectious Diseases Society of America. May 27, 2021. Updated August 12, 2024. Accessed February 10, 2025. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
  6. Recommendations for Antiviral Therapy for Adults with Mild to Moderate COVID-19. Ontario Health. Updated April 2, 2024. Accessed February 11, 2025. https://www.ontariohealth.ca/sites/ontariohealth/files/Recommendations-for-Antiviral-Therapy-for-Adults-with-Mild-to-Moderate-COVID-19.pdf
  7. Chan GCK, Lui GCY, Wong CNS, et al. Safety profile and clinical and virological outcomes of nirmatrelvir-ritonavir treatment in patients with advanced chronic kidney disease and coronavirus disease 2019. Clin Infect Dis. 2023;77(10):1406-1412. doi:10.1093/cid/ciad371
  8. Hiremath S, Blake PG, Yeung A, et al. Early experience with modified dose nirmatrelvir/ritonavir in dialysis patients with Coronavirus Disease 2019. Clin J Am Soc Nephrol. 2023;18(4):485-490. doi:10.2215/CJN.0000000000000107
  9. Lafont E, Blez D, Bildan MA, et al. Nirmatrelvir and ritonavir combination in COVID-19 patients with advanced chronic kidney disease. Clin Infect Dis. 2024;79(3):798-800. doi:10.1093/cid/ciad785
  10. Yan J, Cai H, Wang J, et al. Nirmatrelvir/ritonavir for patients with SARS-CoV-2 infection and impaired kidney function during the Omicron surge. Front Pharmacol. 2023;14:1147980. Published 2023 Mar 22. doi:10.3389/fphar.2023.1147980
  11. Yang H, Yu X, Hou W, et al. Effectiveness and safety of nirmatrelvir-ritonavir in kidney transplant recipients with severe kidney dysfunction infected with COVID-19. Antimicrob Agents Chemother. 2024;68(3):e0138423. doi:10.1128/aac.01384-23
  12. Toussi SS, Neutel JM, Navarro J, et al. Pharmacokinetics of oral nirmatrelvir/ritonavir, a protease inhibitor for treatment of COVID-19, in subjects with renal impairment. Clin Pharmacol Ther. 2022;112(4):892-900. doi:10.1002/cpt.2688
  13. Chu WM, Wan EYF, Ting Wong ZC, et al. Comparison of safety and efficacy between nirmatrelvir-ritonavir and molnupiravir in the treatment of COVID-19 infection in patients with advanced kidney disease: a retrospective observational study. EClinicalMedicine. 2024;72:102620. doi:10.1016/j.eclinm.2024.102620
  14. Cho WJ, Harden D, Moreno D, Dinulos JE, Hanna PE, Wang Q, Kim AY, Sise ME. Oral antiviral therapies for COVID-19 in patients with advanced chronic kidney disease or kidney failure. Nephrol Dial Transplant. 2023;38(8):1912-1914. doi: 10.1093/ndt/gfad058. PMID: 36948600; PMCID: PMC10387392.
  15. Dong R, Huang Y, Ling X, Li L, Yu W, Jiang S. High concentrations of nirmatrelvir/ritonavir in critically ill patients receiving continuous renal replacement therapy. Int J Antimicrob Agents. 2024;63(1):106997. doi:10.1016/j.ijantimicag.2023.106997

Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

March 2025

The information presented is current as February 7, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.