Drug-Drug Interactions Leading to Tacrolimus Toxicity in a Renal Transplant Patient With COVID-19: The Role of Paxlovid and the Mitigating Use of Phenytoin

Tacrolimus, a calcineurin inhibitor widely used in transplant immunosuppression, requires careful monitoring due to its narrow therapeutic index and metabolism by cytochrome P450 CYP3A4. We present a case of a 72-year-old kidney transplant recipient who developed acute tacrolimus toxicity following treatment with nirmatrelvir/ritonavir (Paxlovid) for COVID-19. The patient presented with altered mental status, acute kidney injury, and supratherapeutic tacrolimus levels (>90 ng/mL). Given persistent toxicity, tacrolimus was held, and intravenous phenytoin was initiated to enhance clearance through CYP3A4 induction. The patient demonstrated improvement in renal function and tacrolimus levels, allowing for cautious reinitiation of immunosuppression. This case highlights the critical need for vigilant monitoring of drug-drug interactions in transplant recipients and the potential role of phenytoin as an effective therapeutic strategy in managing tacrolimus toxicity induced by CYP3A4 inhibitors as well as the urgent need for developing COVID-19 outpatient treatments with minimal interaction with tacrolimus.