Comparison of Immediate- and Extended-Release Tacrolimus Formulations in Deceased-Donor Kidney Transplantation (DDKT)

Background: Standard maintenance immunosuppression in DDKT typically includes tacrolimus, mycophenolate mofetil (MMF), and ±steroids. Tacrolimus is available in three formulations: immediate-release tacrolimus (IR-Tac), including brand-name Prograf and generic tacrolimus, and extended-release tacrolimus (Envarsus XR). Envarsus XR has gained increasing use (15–20% of DDKT recipients at any given time) due to its lower peak levels and potentially reduced side effect profile and making it a preferred option for fast metabolizers. However, comparative analyses of these formulations on DDKT outcomes remain limited. Methods: We analyzed national UNOS data for adult DDKT recipients in the U.S. from 2018–2023, excluding recipients of multi-organ transplants, pediatric patients, and those who received multiple induction agents during the index hospitalization. We included patients who remained on the same tacrolimus and MMF formulation at both discharge and conditionally at 1-year (N: Prograf=11,786; Generic Tacrolimus=28,058; Envarsus XR=7,154). Primary outcomes included unadjusted rates of acute rejection (AR) at 1-year and all-cause (ACGF) and death censored graft failures (DCGF) at last follow-up. Cox proportional hazards models were used to evaluate ACGF and DCGF, adjusted using inverse probability weighting (IPW) to account for differences in donor, recipient, and transplant characteristics. Covariate balance was assessed using standardized mean differences (SMD), with SMD<0.1 indicating good balance. Results: Unadjusted 1-year AR rates were 4.4% (Prograf), 5.5% (Generic Tacrolimus), and 4.8% (Envarsus XR) (p<0.001). Graft failure rates during median 2.6–3 years of follow-up were 11.6%, 10.6%, and 8.1% (p<0.001) for ACGF and 4%, 3.5%, 3% for DCGF, respectively (p=0.001). In IPW-adjusted Cox models, compared to the Prograf reference group, there were no statistically significant differences in ACGF risk (Generic Tacrolimus: HR=0.95, 95% CI: 0.87–1.02, p=0.17; Envarsus XR: HR=0.90, 95% CI: 0.81–1.00, p=0.06) or in DCGF risk (Generic Tacrolimus: HR=0.95, 95% CI: 0.86–1.05, p=0.35; Envarsus XR: HR=0.93, 95% CI: 0.80–1.09, p=0.40). Conclusion: Envarsus XR demonstrates non-inferiority to IR-Tac formulations with respect to acute rejection and graft failure outcomes in DDKT. Funding: Commercial Support - Veloxis Pharmaceuticals, Inc