(941) Fosphenytoin to Potentially Induce Clearance of Tacrolimus Level Secondary to Nirmatrelvir/Ritonavir

Introduction: It is well known that ritonavir is a potent cytochrome P450 (CYP) inhibitor whereas fosphenytoin is known as a CYP inducer, and both can potentially lead to significant drug-drug interactions with medications that are CYP substrates, such as calcineurin inhibitors. This case describes the use of fosphenytoin to aid the clearance of toxic tacrolimus levels in a transplant patient after receiving 5 days of nirmatrelvir/ritonavir for SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

Description: A 73-year-old male with past medical history of end stage renal disease status-post donation after circulatory death kidney transplant in June 2021 and type-2 diabetes mellitus was admitted to the intensive care unit for the management of vasodilatory shock secondary to sepsis, acute kidney injury (AKI) and metabolic encephalopathy. Six days prior to admission the patient was diagnosed with COVID-19 and completed a 5-day course of nirmatrelvir/ritonavir prescribed by the patient’s primary care provider. The initial serum tacrolimus level was 153.1 ng/ml, significantly elevated when compared to an outpatient level of 5.7 ng/ml 10-days prior to admission. On day 2 of admission and with a tacrolimus level of 132.8 ng/ml, the patient was initiated on fosphenytoin 100mg intravenously every 8 hours, for a total of 8 doses due to concern of fosphenytoin’s long half-life and potential to decrease patient’s tacrolimus level below therapeutic and risk of rejection. A repeat tacrolimus level the morning after the last dose of fosphenytoin had demonstrated a decreased in tacrolimus down to 69 ng/ml. On ICU and hospital admission day 10, the patient’s tacrolimus level was therapeutic at 9 ng/ml and oral therapy was resumed on hospital day 14 of admission.

Discussion: Clinicians may consider the use of fosphenytoin in the management of calcineurin inhibitor (CI) toxicity not only for its ability to induce CYP3A4 and reduce overall level of CI’s, but also as an anti-epileptic in the prevention of seizures secondary to neurotoxicity from supratherapeutic CI levels. Involving clinicians who are familiar with CI’s pharmacodynamics in medication changes for patients utilizing these medications is critical to prevent severe medication toxicity.