Tacrolimus Toxicity in COVID-19: Nirmatrelvir/Ritonavir Interaction and Phenytoin Management

Introduction: Drug-drug interactions are a significant concern in transplant medicine, particularly with calcineurin inhibitors like tacrolimus, which are metabolized via CYP3A4. Paxlovid (nirmatrelvir/ritonavir), used for COVID-19, inhibits CYP3A4 and can lead to tacrolimus toxicity in solid organ transplant recipients. Case Description: A 56-year-old man with a history of kidney transplantation on tacrolimus, presented with tremor, headache, and nausea, several days after initiating Paxlovid for mild COVID-19. Laboratory evaluation revealed a tacrolimus trough level of 92 ng/mL (range: 5–15 ng/mL) and elevated serum creatinine. Paxlovid was discontinued, and the patient was treated with phenytoin, a CYP3A4 inducer to accelerate tacrolimus metabolism. Tacrolimus levels and renal function improved within 72 hours. Patient remained stable with no graft dysfunction or infectious complications. Discussion: This case underscores the importance of recognizing clinically significant drug-drug interactions in solid organ transplant recipients in the setting of acute illnesses such as COVID-19. Tacrolimus is extensively metabolized by the cytochrome P450 3A4 (CYP3A4). Ritonavir, a component of Paxlovid, is a CYP3A4 inhibitor and can drastically reduce tacrolimus clearance, resulting in rapid and dangerous accumulation. In this patient, the use of Paxlovid without appropriate dose adjustment or monitoring of tacrolimus led to supratherapeutic levels and acute nephrotoxicity. Although guidelines recommend holding or adjusting tacrolimus during co-administration with ritonavir, real-world challenges, such as lack of awareness, delayed recognition, and logistical barriers to therapeutic drug monitoring, can result in adverse outcomes. This case also highlights an underutilized yet effective therapeutic option: the use of phenytoin, a CYP3A4 inducer. Phenytoin accelerated tacrolimus clearance, contributing to a timely reduction in levels and symptomatic improvement, without precipitating rejection or compromising immunosuppression. Furthermore, this case adds to a growing body of evidence suggesting that in select patients with calcineurin inhibitor toxicity, enzyme inducers may play a role in management when time-sensitive reversal is needed. However, such strategies require multidisciplinary coordination and careful risk-benefit assessment.