D327 - Treatment of Acute Tacrolimus Toxicity with Phenytoin After Itraconazole Therapy in a Kidney Transplant Recipient

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Author Block: M. Pittappilly, B. Tamimi, M. Sharshir, D. Khirfan, B. Alper, Tulane Transplant Institute at East Jefferson Hospital, New Orleans, LA
*Purpose: Tacrolimus is a key immunosuppressant used in kidney transplantation that is metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Many medications can interfere with the CYP3A4 enzyme by either inhibiting or inducing its activity. Use of common CYP3A4 inhibitors including the azole antifungals can lead to supratherapeutic tacrolimus levels. We present a case of acute tacrolimus toxicity resulting from itraconazole therapy requiring use of oral phenytoin for enzyme induction in a kidney transplant recipient.
*Methods: An 84-year-old male with history of end stage renal disease secondary to type 2 diabetes mellitus status post living donor kidney transplantation in 2021, heart failure with reduced ejection fraction and chronic nodular skin lesions of left arm due to invasive fungal infection on itraconazole was admitted with shortness of breath and found to have acute kidney injury and supratherapeutic tacrolimus level > 30 ng/mL.
*Results: Tacrolimus and itraconazole were immediately discontinued. Given worsening renal function and tacrolimus level persistently > 30 ng/mL, oral phenytoin 200 mg twice daily was started. The patient received eight doses of phenytoin and his tacrolimus levels down trended to a therapeutic range. In addition, kidney function improved as tacrolimus levels decreased. No side effects were observed. A punch biopsy of the lesions showed hyalohyphomycosis and fungal tissue culture identified purpureocillium lilacinum. Further history revealed pot gardening for the past year. Isavuconazole, a moderate CYP3A4 inhibitor, was started based on susceptibility testing and tacrolimus was cautiously restarted at a lower dose.
*Conclusions: This case highlights the use of phenytoin, a potent CYP3A4 inducer, to manage acute tacrolimus toxicity in kidney transplant recipients. The route of administration of phenytoin has been shown to influence outcomes with the IV route associated with more rapid correction but with more side effects. Our case adds to the body of literature that oral phenytoin appears to be a safe and effective strategy to rapidly reverse tacrolimus toxicity. Given increased incidence of opportunistic infections in kidney transplant recipients, careful selection of antifungals with consideration for less potent inhibition of CYP3A4 enzyme along with serial therapeutic monitoring can prevent Tacrolimus toxicity.