In a kidney transplant recipient on tacrolimus who develops mild‑to‑moderate COVID‑19 within five days and has an estimated glomerular filtration rate ≥30 mL/min, should I prescribe Paxlovid (nirmatrelvir + ritonavir) and how should I adjust the dosing and manage the immunosuppressant drug interactions?

Paxlovid for Kidney Transplant Recipients

Yes, prescribe Paxlovid for this kidney transplant recipient with mild-to-moderate COVID-19, but you must temporarily discontinue tacrolimus during the 5-day treatment course and carefully manage its resumption to avoid life-threatening drug toxicity. 1, 2, 3

Patient Eligibility and Treatment Indication

• Kidney transplant recipients are high-risk patients who meet criteria for Paxlovid treatment due to their immunocompromised status, even if vaccinated. 1, 4
• With an eGFR ≥30 mL/min and symptom onset within 5 days, this patient qualifies for standard or adjusted dosing depending on exact renal function. 1, 2
• The American College of Physicians strongly recommends Paxlovid for high-risk patients with non-severe COVID-19 to reduce hospitalization and death. 1, 4

Dosing Based on Renal Function

For eGFR ≥60 mL/min (Normal Renal Function)

• Standard dose: nirmatrelvir 300 mg (two 150 mg tablets) with ritonavir 100 mg (one tablet) orally twice daily for 5 days. 1, 2

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

• Reduced dose: nirmatrelvir 150 mg (one 150 mg tablet) with ritonavir 100 mg (one tablet) orally twice daily for 5 days. 1, 2
• This dose reduction is mandatory to prevent drug accumulation and toxicity. 1

For eGFR <30 mL/min (Severe Renal Impairment)

• Day 1: nirmatrelvir 300 mg with ritonavir 100 mg once daily; Days 2-5: nirmatrelvir 150 mg with ritonavir 100 mg once daily. 2
• Recent evidence from 40 kidney transplant recipients with severe renal dysfunction showed this modified dosing was well-tolerated with no grade ≥3 adverse events. 3

Critical Tacrolimus Management Protocol

During Paxlovid Treatment (Days 1-5)

Hold tacrolimus completely during the entire 5-day Paxlovid course. 3, 5, 6

• Ritonavir is a potent irreversible CYP3A4 inhibitor that causes dramatic tacrolimus elevation, leading to toxicity, acute kidney injury, and potentially life-threatening complications. 2, 5, 7
• Case reports document abruptly high tacrolimus levels (often >30 ng/mL), significant symptoms, and acute kidney injury when tacrolimus was continued during Paxlovid. 7, 8
• In a multicenter study of 40 kidney transplant recipients, all patients temporarily discontinued immunosuppressants during Paxlovid with no disease progression in moderate COVID-19 cases. 3

After Completing Paxlovid (Post-Day 5)

Resume tacrolimus 24 hours after the last Paxlovid dose at 50% of the previous maintenance dose. 5, 6

• Do NOT resume at full dose—one patient who restarted at usual maintenance dose developed toxic levels. 5
• Ritonavir's CYP3A4 inhibition persists for several days after discontinuation, requiring continued caution. 1, 6

Monitoring Strategy

Check tacrolimus trough levels 48-72 hours after resuming tacrolimus, then every 2-3 days until stable therapeutic levels are achieved. 5, 8, 6

• Monitor serum creatinine closely for acute kidney injury, which can result from tacrolimus toxicity. 7, 8
• Some patients experienced lower-than-expected tacrolimus levels after the therapeutic break, requiring dose adjustments upward. 3, 5
• Adjust tacrolimus dose based on trough levels and clinical status, aiming for the patient's usual therapeutic target range. 5, 6

Management of Other Immunosuppressants

Mycophenolate and Azathioprine

• Consider holding or reducing these agents during Paxlovid treatment, particularly if the patient develops pneumonia, lymphopenia, or persistent fever. 9
• These can be safely interrupted for 5 days without immediate rejection risk. 9

Corticosteroids

• Continue maintenance corticosteroids at a sufficient dose to avoid adrenal insufficiency. 9
• Do not discontinue steroids abruptly, as this can cause adrenal crisis. 9

Drug Interaction Screening

Before prescribing Paxlovid, use the Liverpool COVID-19 Drug Interaction Tool to systematically check all concomitant medications. 1, 4, 6

• Ritonavir causes potentially life-threatening interactions with drugs metabolized by CYP3A4, including statins (especially simvastatin and lovastatin), certain antiarrhythmics, and sedatives. 1, 2, 6
• Medications highly dependent on CYP3A4 for clearance may require temporary discontinuation, dose adjustment, or additional monitoring. 2, 6
• The FDA black box warning emphasizes that ritonavir may lead to severe, life-threatening, or fatal events from drug interactions. 2

Timing and Administration

• Initiate Paxlovid as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset. 1, 4, 2
• Treatment beyond 5 days of symptom onset is not supported by efficacy data. 1, 4
• Administer with or without food at approximately the same time each day. 4, 2

Safety Monitoring During Treatment

• Monitor for dysgeusia (altered taste) and diarrhea, the most common adverse effects, which rarely require discontinuation. 1, 2
• Watch for signs of hypersensitivity reactions, including anaphylaxis, Stevens-Johnson syndrome, or toxic epidermal necrolysis—if these occur, immediately discontinue Paxlovid. 2
• Monitor hepatic function if baseline abnormalities are present, as ritonavir can cause hepatotoxicity. 2
• Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury. 1

Common Pitfalls to Avoid

1. Never continue tacrolimus at full dose during Paxlovid—this consistently causes toxicity. 5, 7, 8
2. Never resume tacrolimus at full maintenance dose immediately after Paxlovid—ritonavir's effects persist for days. 5, 6
3. Never prescribe Paxlovid without checking drug interactions—the FDA mandates this due to life-threatening risks. 2, 6
4. Never use Paxlovid in patients with severe hepatic impairment (Child-Pugh Class C)—it is not recommended due to lack of safety data. 1, 2
5. Do not abruptly discontinue corticosteroids—maintain sufficient doses to prevent adrenal insufficiency. 9

Alternative Considerations

• If Paxlovid cannot be used due to unmanageable drug interactions, remdesivir is the preferred alternative, particularly for transplant recipients. 4
• Molnupiravir is a less effective oral option when Paxlovid is unavailable or contraindicated. 4