Risks of Tacrolimus and Paxlovid Therapy in SARS-CoV-2 Positive Transplant Recipients: A Case Discussion and Institutional Data Review

Abstract Introduction/Objective Transplant recipients maintained on immunosuppressants like tacrolimus continue to be at high risk for morbidity due to SARS-CoV-2 infection and are strong candidates for antiviral therapies. However, co- administration of the antiviral Paxlovid (nirmatrelvir/ritonavir) poses a significant risk to these patients due to ritonavir- mediated inhibition of CYP3A, an important mediator of tacrolimus metabolism. Consequently, Paxlovid therapy in post-organ transplant patients on tacrolimus requires careful consideration. Our investigation aims to assess the continuing risk posed by this drug-drug interaction and better understand clinical circumstances linked to critically high tacrolimus levels due to Paxlovid co-administration. Methods/Case Report We conducted a large-scale retrospective analysis of tacrolimus measurements at the University of Michigan Medicine beginning in January 2020. We also performed a detailed review of patients with critically high tacrolimus levels coinciding with Paxlovid administration. Results (if a Case Study enter NA) Of 39,752 tacrolimus measurements examined, 682 correspond to 329 patients with recent positive SARS-CoV-2 nucleic acid testing, and 37 correspond to 18 patients with documented Paxlovid co- administration. Patients receiving concurrent Paxlovid and tacrolimus demonstrate 1.6- and 1.8-fold higher mean tacrolimus levels (14.1 ng/mL, p = 3e-5) compared to other SARS-CoV-2 positive (8.7 ng/mL) and negative/untested (7.9 ng/mL) patients, respectively. Among SARS-CoV-2 patients, those prescribed Paxlovid are more likely to present with supratherapeutic tacrolimus levels (OR 4.1, 95% CI 1.6 – 10.7). A detailed case review of three organ transplant recipients presenting with tacrolimus levels >60 ng/mL and creatinine levels increased by 0.45 ± 0.27 mg/dL from baseline shows Paxlovid was prescribed at outside facilities, and regular tacrolimus dose was continued. Three other patients exhibited supratherapeutic tacrolimus levels (20 – 30 ng/mL), and creatinine levels increased by 0.41 ± 0.23 mg/dL from baseline despite dose reduction or cessation before initiating Paxlovid. Conclusion Our findings highlight the importance of communication between primary and tertiary care providers and caution when prescribing Paxlovid in populations managed with tacrolimus therapy.