The Highest Tacrolimus Level Ever Recorded

Introduction: Tacrolimus is a calcineurin inhibitor commonly used to prevent kidney transplant rejection. At toxic levels, it can cause nephrotoxicity via constriction of the afferent arteriole, as well as neurotoxicity such as tremor, headaches, seizures, PRES, and other adverse events. Because of its metabolism through the cyp3A4 system, there are many drug-drug interactions that can lead to toxicity via inhibition of the cyp3A4 enzyme. One such inhibitor is ritonavir, which is used in the COVID therapeutic Paxlovid as a Cyp3A4 inhibitor. In this case report we describe a case of tacrolimus toxicity with the highest reported tacrolimus level to date and its associated toxicities. Case Description: This patient is a 45 year old woman with a history of ESRD secondary to presumed diabetic nephropathy and hypertension, who underwent a deceased donor kidney transplant 6 years prior to presentation. She was maintained on Envarsus 14mg daily, cellcept 1000mg BID, and prednisone 5mg daily. She tested positive for COVID 4 days prior to presentation and had received 4 doses of nirmatrelvir/ritonavir (Paxlovid). The patient presented to the ED with diarrhea, emesis, fatigue, and fine intention tremor. She was found to have a tacrolimus trough level of 218.3ng/mL. She was noted to have an AKI on CKD with her peak creatinine reaching 5.04. The envarsus and paxlovid were stopped. She was given 200mg IV phenytoin in successively increasing intervals to act as a cyp3A4 inducer. Her tacrolimus levels gradually improved back to therapeutic levels and her AKI resolved. She did not suffer from TMA or PRES. Her neurologic symptoms included only a mild tremor that resolved. Discussion: This case demonstrates several learning points: 1) Highlights the importance of drug-drug interactions, especially between Paxlovid and tacrolimus. 2) demonstrates the ability to use cyp3A4 inducers in a therapeutic role for tacrolimus nephrotoxicity. 3) Hints that there may be less neurotoxicity with envarsus compared to immediate-release tacrolimus.