Is a dosing schedule of 2 nirmatrelvir (generic name) and 1 ritonavir (generic name) once daily acceptable for patients with impaired renal function due to COVID-19?

Nirmatrelvir/Ritonavir Dosing in Renal Impairment for COVID-19

The once-daily dosing schedule of 2 nirmatrelvir tablets (150 mg each) and 1 ritonavir tablet (100 mg) is NOT an acceptable dosing regimen for patients with renal impairment in COVID-19. 1, 2 The FDA-approved dosing for patients with renal impairment requires specific dose adjustments that differ from this proposed regimen.

Correct Dosing for Renal Impairment

Moderate Renal Impairment (eGFR 30-59 mL/min)

• Recommended dose: 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days 1, 2
• This reduced dose maintains appropriate therapeutic levels while minimizing toxicity risk

Severe Renal Impairment (eGFR <30 mL/min) including patients on hemodialysis

• Day 1: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once
• Days 2-5: 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily 2
• For hemodialysis patients, the dose should be administered after hemodialysis 2

Pharmacokinetic Rationale

The FDA-approved dosing is based on pharmacokinetic studies showing that nirmatrelvir exposure increases significantly with declining renal function:

• In moderate renal impairment: 87% higher AUC compared to normal renal function 2, 3
• In severe renal impairment: 204% higher AUC compared to normal renal function 2, 3

A phase I study demonstrated that renal clearance of nirmatrelvir decreases by 47% in moderate impairment and 80% in severe impairment compared to normal renal function 3. This necessitates the specific dose adjustments outlined above to maintain efficacy while avoiding toxicity.

Clinical Evidence Supporting Modified Dosing

Clinical experience supports the safety and efficacy of the FDA-approved modified dosing regimens:

• A study of 134 dialysis patients with COVID-19 who received the modified dose regimen (300/100 mg on day 1, followed by 150/100 mg daily for days 2-5) found that 96% completed the course with no COVID-19-related deaths in the 30-day follow-up period 4

• Another study comparing nirmatrelvir-ritonavir to molnupiravir in patients with advanced kidney disease (eGFR <30 ml/min) found that properly dosed nirmatrelvir-ritonavir was associated with significantly reduced risk of all-cause mortality (HR: 0.624) and hospitalization (HR: 0.782) 5

Common Pitfalls to Avoid

1. Incorrect frequency: The proposed once-daily dosing for moderate renal impairment is inadequate - twice-daily administration is required to maintain therapeutic levels 1, 2

2. Drug interactions: Ritonavir is a strong CYP3A inhibitor that can cause significant drug-drug interactions, particularly problematic in patients with kidney disease who often take multiple medications 6

3. Failure to adjust for hemodialysis: For patients on hemodialysis, administration should occur after dialysis sessions 2

4. Assuming all renal impairment requires the same dosing: Different dosing schedules are required for moderate versus severe impairment 2

Monitoring Recommendations

• Assess for drug-drug interactions before initiating therapy (using resources like the Liverpool COVID-19 Drug Interaction Tool) 1, 6
• Monitor for adverse effects, particularly in patients with severe renal impairment
• Ensure patients complete the full 5-day treatment course to maximize viral clearance 2

The evidence clearly demonstrates that proper dosing adjustments for renal impairment are essential for both safety and efficacy of nirmatrelvir/ritonavir in COVID-19 patients, and the proposed once-daily regimen of 2 nirmatrelvir and 1 ritonavir does not align with evidence-based recommendations.