D326 - Tic-Tac-Tox: Severe Tacrolimus Toxicity After a Single Dose of Nirmatrelvir-Ritonavir in a Kidney Transplant Recipient

View session detail

Author Block: C. T. Faldu, E. Bassil, A. Gogoli, A. Nishio-Lucar, University of Virginia, Charlottesville, VA
*Purpose: Nirmatrelvir-ritonavir is a known strong inhibitor of cytochrome P450 3A/3A4 enzyme. As tacrolimus is metabolized by the same system, concomitant use can result in supratherapeutic levels of tacrolimus if not adjusted and monitored closely. Case reports have described abrupt elevation of serum tacrolimus levels a few days after starting nirmatrelvir-ritonavir. We describe a case of severe toxicity with just one dose of the combination antiviral.
*Methods: A 63-year-old male with ESRD status post kidney transplantation nine years prior, and a recent COVID-19 infection was admitted with falls, leg weakness, nausea, vomiting. Labs were notable for acute kidney injury (serum creatinine 2.4 mg/dL with a baseline of 1.5 mg/dL) and a tacrolimus level of > 40.0 ng/mL (baseline levels of 4 to 7 ng/mL). Of note, the current laboratory range was unable to report a level beyond the value of 40.0 ng/mL. He was given one dose of nirmatrelvir-ritonavir a week prior along with his usual tacrolimus dose of 1mg in the morning and 1.5mg in the evening.
*Results: Tacrolimus was held on the day of presentation (Day 0). Fluids were given with improvement of symptoms. Serum tacrolimus levels improved and tacrolimus 1mg orally twice daily was restarted on Day 4 (see Figure 1). On Day 6, creatinine returned to baseline with the resolution of all symptoms.
*Conclusions: Severe tacrolimus toxicity following co-administration with ritonavir-containing regimens resulting in acute kidney injury, neurotoxicity (tremors, confusion, or seizures), and gastrointestinal symptoms, even when tacrolimus is withheld during ritonavir therapy. Symptoms of toxicity can often be misdiagnosed and can lead to delays in management. The mechanism is attributed to ritonavir’s potent inhibition of both CYP3A4 and P-glycoprotein, leading to dramatically reduced tacrolimus clearance and prolonged half-life.
Management requires immediate discontinuation of tacrolimus and ritonavir, aggressive supportive care, and, in severe or persistent cases, the use of CYP3A4 inducers such as phenytoin or rifampin to accelerate tacrolimus metabolism, though the effect of enzyme inducers may be delayed due to the persistent inhibitory effect of ritonavir and need for prolonged monitoring after its discontinuation.
Tacrolimus toxicity requires a high degree of clinical suspicion and comprehensive patient assessment. Providers and pharmacists must remain vigilant for drug interactions when introducing new medications in solid organ transplant recipients given tacrolimus narrow therapeutic index