Tacrolimus Toxicity Due to Unrecognized Significance of Nirmatrelvir-Ritonavir Interaction in a Case Series of Solid Organ Transplant Recipients

ABSTRACT

Introduction: Nirmatrelvir-ritonovir (NIM-RTV) for COVID-19 increases tacrolimus (XR-Tac;IR-Tac) concentrations. Increased availability of NIM-RTV and ongoing COVID-19 infections, poses a significant risk to solid organ transplant (SOT) recipients. Case Case 1 describes a 66-year-old (yo) male 1.5 years post-liver transplant on XR-Tac (goal 4-8 ng/mL). After 4 doses of NIM-RTV, XR-Tac was held and NIM-RTV continued. His tacrolimus level was 23.9 ng/mL and SCr 2.4 mg/dL (baseline 1.4 mg/dL) 3 days after holding XR-Tac. Case 2 was a 60 yo male 7 months post-lung transplant that received 2 doses of NIM-RTV + IR-Tac (goal 8-10 ng/mL). He experienced AKI (SCr 1.3 mg/dL, baseline 1.0 mg/dL) with a tacrolimus level >60 ng/mL. Tacrolimus and NIM-RTV were held and phenytoin initiated. The patient's SCr returned to baseline 5 days later. Case 3 includes a 53 yo male 2.5 years post-kidney transplant on XRTac (goal 4-6 ng/mL). Following 2 doses of NIM-RTV, he was hospitalized with a tacrolimus level >60 ng/mL, AKI (SCr 2.2 mg/dL, baseline 1.7 mg/dL) and nausea/vomiting. Both medications were held and phenytoin initiated. Tacrolimus and SCr returned to baseline 6 days later. Case 4 was a 75 yo female 19 years post-heart transplant on IRTac (goal 4-6 ng/mL). After 4 doses of NIM-RTV, she required hospital admission for AKI and vision changes. Tacrolimus level was >60 ng/mL. Phenytoin was started as IR-Tac and NIM-RTV were stopped. Tacrolimus, SCr, and vision returned to normal 4 days later. Discussion(s) Limited data and knowledge regarding severity of concomitant NIM-RTV/tacrolimus exists. Furthermore, there is no data describing the use of the CYP3A4 inducer phenytoin to reverse tacrolimus toxicity. Conclusion(s) Even after only a few doses of concomitant NIM-RTV and tacrolimus, there is a significant risk of tacrolimus toxicity. Phenytoin induction may serve to minimize the toxicities associated with supratherapeutic troughs above the upper limit of detection.