Paxlovid (Nirmatrelvir/Ritonavir) and Tacrolimus Toxicity in Solid-Organ Transplant Recipients: A Multicenter Analysis

Background: Nirmatrelvir/ritonavir (N/R) is an antiviral for COVID-19 that can increase tacrolimus levels by inhibiting CYP3A enzymes in transplant recipients. A recent case of fatal tacrolimus toxicity induced by N/R inspired this retrospective multicenter cohort analysis of N/R usage in solid organ transplant recipients. Methods: Data for the study was obtained using TriNetX and included 103 healthcare organizations (HCOs) between March 2020 and May 2025. We used ICD10 diagnoses of transplant status (kidney, heart, lung, liver, pancreas) at least one month before the COVID-19 diagnosis to identify suitable cases. Cases were then divided into two groups based on whether they had received N/R within two weeks of the diagnosis. Tacrolimus levels two weeks after COVID-19 diagnosis were analyzed. Tacrolimus levels > 20 ng/dL was defined as tacrolimus toxicity. Propensity score analysis matched the two groups on demographics and clinical characteristics. Chi square with odds ratio was used for binary variables and t-tests were used for continuous variables. Results: We identified 53,562 transplant recipients who did not receive N/R for COVID-19 and 726 transplant recipients who received N/R. After propensity score matching, those who received N/R (n= 725) had higher mean tacrolimus levels (9.3 ng/mL) than those (n=725) who did not receive N/R (7.04 ng/mL; p <0.001). Solid organ transplant recipients receiving N/R had higher odds of tacrolimus toxicity than those who did not (OR 2.2, 95% CI [1.33 - 3.72] p = 0.002). Kidney transplant recipients who received N/R (n=513) had a higher odds of tacrolimus toxicity than other (n=243) solid organ transplant recipients (OR 2.0, 95% CI [1.00 - 4.11]; p = 0.047). The administration of N/R did not significantly impact the incidence of acute kidney injury or neurologic events. Conclusion: N/R to treat COVID-19 in transplant recipients is uncommon (1.3%) but appears to be relatively safe. Nonetheless, for those receiving N/R, tacrolimus levels were higher including those > 20 ng/mL. N/R and tacrolimus protocols may vary among HCOs and those receiving N/R may have been healthier or more closely monitored. We recommend careful monitoring of tacrolimus levels and a phenytoin protocol for severe tacrolimus toxicity.