Safety and Efficacy of Reduced Prolonged-release Tacrolimus Exposure in De Novo Kidney Transplantation: A Randomized, Open-label, Pilot Study in Asia—OPTIMIZE Study

BACKGROUND: A multicenter, randomized, open-label, parallel group, pilot, 52-week study in Asian countries that assessed the renal function, efficacy, and safety of reduced-exposure versus standard-exposure prolonged-release tacrolimus (PR-T) in adult kidney transplant recipients (KTRs). METHODS: Posttransplantation, KTRs received PR-T from weeks 0 to 4 (initial dose, 0.2–0.3 mg/kg; target trough level, 6–10 ng/mL). At week 4, KTRs were randomized (1:1) to receive reduced-exposure PR-T (target 4–6 ng/mL, weeks 4–12; 3–5 ng/mL, weeks 12–52) or standard-exposure PR-T (target: 6–10 ng/mL, weeks 4–52). Primary end point: estimated glomerular filtration rate (eGFR) over 52 weeks. Secondary end points (week 52) included creatinine clearance, serum creatinine, graft/patient survival, biopsy-confirmed acute rejection (AR), composite of graft loss/patient death/biopsy-confirmed AR, and steroid-resistant AR. Treatment-emergent adverse events were recorded. RESULTS: Sixty-six KTRs received PR-T (reduced-exposure, n = 32; standard-exposure, n = 34) and were analyzed. After per-protocol dose adjustment, mean ± standard deviation tacrolimus trough level was lower with reduced- versus standard-exposure PR-T (week 52, 4.5 ± 1.1 ng/mL vs 8.0 ± 2.2 ng/mL). In the reduced- versus standard-exposure group, eGFR was similar at weeks 8 to 52 (overall least-square mean difference, –2.82; 95% confidence interval, −7.91 to 2.27; P = 0.272). At week 52, there was no significant difference in creatinine clearance (P = 0.375) or serum creatinine (P = 0.547) between groups. All grafts/patients survived, no steroid-resistant AR was reported, and 4 and 3 patients had AR in reduced- and standard-exposure groups, respectively. Drug-related treatment-emergent adverse events were reported in 34.4% and 38.2% of patients, respectively. CONCLUSIONS: Reducing exposure to PR-T resulted in a clinically acceptable short-term safety profile and was generally as effective as standard tacrolimus exposure for Asian patients.