A Case Report of Successful Use of Phenytoin/Fosphenytoin in a Pediatric Kidney Transplant Recipient With Nirmatrelvir/Ritonavir-Induced Tacrolimus Allograft Injury.

Background: Paxlovid, a fixed combination nirmatrelvir and ritonavir (NIM-RTV), is a potent inhibitor of cytochrome P450 3A4 (CYP3A4) isoenzyme. It is approved for the treatment of mild to moderate COVID-19 infections in patients at risk for serious infection. The metabolism of tacrolimus, a CYP3A4 substrate, is significantly reduced in those receiving NIM-RTV. Coadministration of NIM-RTV without tacrolimus dose reduction may result in toxicity. CYP3A4-inducing medications, including phenytoin, fosphenytoin or rifampin, may reverse toxicity while achieving rapid clearance.

Case presentation: A 14-year-old, 66.5 kg African American female with a history of chronic kidney disease stage 5 secondary to collapsing focal segmental glomerulosclerosis (FSGS) underwent an uncomplicated deceased donor kidney transplant at 12 years of age. Approximately 2.5 years after transplant, she tested positive for COVID-19. NIM-RTV was prescribed through a local pharmacy. She presented 3.5 days later with nausea, vomiting, fatigue, and oligo-anuria with acute kidney injury (AKI) and creatinine of 2.6 mg/dL from baseline of 0.7 mg/dL. Tacrolimus level was > 60 ng/mL. Phenytoin/fosphenytoin was initiated to induce tacrolimus clearance due to sustained AKI and neurological risk. Within 36 h, her tacrolimus level was 38 ng/mLwith improved urine output. After 3 days, her tacrolimus level 11.9 ng/mL and serum creatinine was near baseline.

Conclusions: To our knowledge, this is the first report of a pediatric kidney transplant patient with tacrolimus toxicity secondary to NIM-RTV therapy utilizing phenytoin/fosphenytoin to induce tacrolimus metabolism and prevent further toxicity. Heightened awareness of this interaction is paramount to reduce allograft injury and promote patient safety.