Phenytoin enzyme induction for management of supratherapeutic tacrolimus levels due to drug-drug interaction with nirmatrelvir/ritonavir: Case series and discussion

Nirmatrelvir/ritonavir is one of few options for outpatient treatment of COVID-19, but its use has been limited in transplant recipients due to significant drug interactions with immunosuppressants. Tacrolimus toxicity is possible when the drug is coadministered with nirmatrelvir/ritonavir and may require urgent reduction of tacrolimus levels. This case series describes the use of phenytoin for enzyme induction in 5 adult solid organ transplant recipients with supratherapeutic tacrolimus levels resulting from coadministration with nirmatrelvir/ritonavir. Solid organ transplant recipients are at high risk for complications related to COVID-19. Outpatient treatment options are limited, and therapeutic drug monitoring is complex in patients requiring quarantine. The 5 solid organ transplant recipients described herein were initiated on nirmatrelvir/ritonavir in the outpatient setting and subsequently presented with supratherapeutic tacrolimus concentrations greater than 59 ng/mL and developed signs and symptoms of tacrolimus toxicity. In all patients, nirmatrelvir/ritonavir and tacrolimus were discontinued, and oral phenytoin (200-400 mg/day) was given for 2 to 4 days. Tacrolimus was resumed once tacrolimus levels decreased to appropriate levels. These observations demonstrate that metabolism induction using phenytoin may be a useful strategy in the setting of supratherapeutic tacrolimus levels resulting from concomitant administration with nirmatrelvir/ritonavir.