*Purpose: Sirolimus (SIR), a mammalian target of rapamycin inhibitor (mTORi), may be used with or without a calcineurin inhibitor after heart transplant (HT). The anti-proliferative properties & 72-hour half-life (T1/2) that make SIR desirable to provide uniform drug exposure & attenuate cardiac allograft vasculopathy add complications when surgical needs or toxicities arise.^1,2 SIR-related wound healing impairment necessitates cessation before invasive procedures, yet managing long-acting SIR in these settings is complex due a large volume of distribution & vulnerability to interactions with CYP3A4 inhibitors, prolonging T1/2.² Phenytoin (PHY), a potent inducer of CYP3A4, has been used to speed tacrolimus (FK) clearance.³ Interaction between PHY & SIR is reported.⁴ Strategic use of PHY to clear SIR is not described.

*Methods: Case review leveraging PHY-inducing effects to expedite SIR & FK elimination while awaiting urgent thoracotomy for mucormycosis.

*Results: The patient developed invasive pulmonary mucormycosis 3 years post-HT. Supratherapeutic levels on admission were SIR 20 ng/mL & FK 15 ng/mL with mycophenolate 500 mg twice daily & prednisone 5 mg twice daily. Treatment was initiated with CYP3A4-inhibiting isavuconazonium sulfate (ISU) & amphotericin B irrigation. Infected lung segment resection was delayed for wound healing risks of SIR. To hasten SIR elimination via CYP3A4 induction, fosPHY load then PHY 100 mg orally thrice daily was initiated on day 5. To maintain infection treatment while inducing metabolism, ISU was converted to systemic amphotericin B. Figure 1 describes SIR, FK, ISU & PHY courses. The calculated T1/2 was shorted from 440 hours on ISU days 3-5 to 32 hours days 7-10 (allowing time for induction). On day 14 thoracotomy & left upper lobectomy were successfully performed with FK & SIR unquantifiable.

*Conclusions: This case illustrates effective induction SIR & FK metabolism using PHY. In the era of CYP 3A4-inhibiting nirmatrelvir-ritonavir availability for COVID-19, strategies to address inadvertent calcineurin inhibitor or mTORi toxicity are paramount. Employing this approach when needing to clear drugs quickly may be beneficial.

¹Asleh R, Briasoulis A, Kremers WK, et al. J Am Coll Cardiol. 2018;71(6):636-650. ²Product Information: RAPAMUNE oral solution oral tablets, sirolimus oral solution oral tablets. Pfizer, Inc. (per manufacturer), Philadelphia, PA, 2015.³Jantz AS, Patel SJ, Suki WN, et al. Case Rep Transplant. 2013;2013:375263.⁴Bates D, Burak KW, Coffin CS, et al. Can J Hosp Pharm. 2011;64(4):271-274.

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