What is the recommended dosing of Paxlovid (nirmatrelvir and ritonavir) for Covid-19 patients with impaired renal function?

Paxlovid Dosing in COVID-19 Patients with Renal Impairment

For patients with moderate renal impairment (eGFR 30-59 mL/min), reduce the Paxlovid dose to 150 mg nirmatrelvir with 100 mg ritonavir twice daily for 5 days; for severe renal impairment (eGFR <30 mL/min), give 300 mg nirmatrelvir with 100 mg ritonavir once on day 1, then 150 mg nirmatrelvir with 100 mg ritonavir once daily on days 2-5. 1

Standard Dosing for Normal Renal Function

• Patients with normal renal function or mild impairment (eGFR ≥60 mL/min) should receive 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days 1, 2
• Treatment must be initiated within 5 days of symptom onset and administered at approximately the same time each day 1, 2
• All three tablets should be taken together, with or without food 1

Dose Adjustments for Renal Impairment

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

• Reduce to 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily for all 5 days 1, 2
• This dose reduction is necessary because nirmatrelvir is primarily eliminated renally when co-administered with ritonavir, and accumulation can occur with impaired renal function 3
• Population pharmacokinetic modeling supports this reduced dose maintains therapeutic concentrations while avoiding excessive drug exposure 4

Severe Renal Impairment (eGFR <30 mL/min)

• Day 1: Give 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) as a single dose 1
• Days 2-5: Give 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily 1
• For patients on hemodialysis, administer the dose after dialysis on dialysis days 1

Contraindication in Severe Renal Impairment

• Paxlovid was contraindicated in patients with severe renal impairment in some early protocols, and prescribing errors have been documented where the drug was given despite this contraindication 5
• However, the current FDA label provides specific dosing for severe renal impairment rather than contraindicating use, reflecting updated evidence 1

Clinical Pharmacology Rationale

• Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics and reaches maximum concentration of 3.43 µg/mL in approximately 3 hours on day 5 of standard dosing 3
• When co-administered with ritonavir, renal elimination becomes the primary route of nirmatrelvir clearance because ritonavir inhibits CYP3A4-mediated metabolism 3
• Nirmatrelvir clearance increases proportionally with creatinine clearance up to 70 mL/min/1.73 m², then plateaus above this breakpoint 4
• Patients older than 65 years have significantly higher plasma trough concentrations (odds ratio 11.2 for excessive levels) and require careful monitoring, especially when combined with renal impairment 6

Critical Safety Considerations

• Always assess renal function before prescribing using estimated glomerular filtration rate (eGFR) to determine appropriate dosing 1
• Monitor for drug accumulation signs including dysgeusia and diarrhea, which are the most common adverse effects but can be more pronounced with higher drug levels 1, 6
• Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury 7
• Check for renally eliminated co-medications that may also accumulate and increase risk of adverse effects when combined with impaired renal function 6

Drug Interaction Management in Renal Impairment

• Use the Liverpool COVID-19 Drug Interaction Tool before prescribing to identify contraindicated medications and those requiring dose adjustment 2, 8
• Ritonavir is a strong CYP3A inhibitor causing numerous drug-drug interactions that persist during treatment and for several days after completion 2, 8
• Pharmacist involvement is essential when prescribing Paxlovid in patients with renal impairment, as 87.1% of patients require interventions to prevent drug-related problems 5
• In patients with both renal impairment and significant drug interactions, consider whether alternative COVID-19 therapies may be safer 5

Common Pitfalls to Avoid

• Do not use standard dosing in moderate or severe renal impairment, as this leads to excessive drug accumulation and increased toxicity risk 1, 6
• Do not forget to adjust timing to once daily in severe renal impairment after day 1, as twice daily dosing will cause dangerous accumulation 1
• Do not overlook acute kidney injury that may develop during COVID-19 illness, requiring dose adjustment mid-treatment 7
• Do not prescribe without checking drug interactions, as the combination of renal impairment and interacting medications was present in 24.3% of patients in one study 5