#4233 FIXED LOW DOSE VERSUS CONCENTRATION-CONTROLLED INITIAL TACROLIMUS DOSING: RESULTS FROM A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL (SLOW&LOW STUDY)

Abstract

Abstract Background and Aims Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied. Based on the assumption that current treatment protocols using frequent trough level determinations in the first week after transplantation may cause overexposure related nephrotoxic side effects and frequent monitoring is costly and not supported by basic pharmacokinetic principles, we had the hypothesis that early low and fixed tacrolimus dosing may be a safe and practical alternative. Method In this open-label, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9 ng/ml; arm A), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7 ng/ml; arm B, see Figure 1). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure or death at 6 months with a non-inferiority margin of 12.5 %. Results The combined primary endpoint in arm B was non-inferior compared to the control arm A (22.1 % versus 20.2 %; difference 95 % CI: 1.9- 8.8 %). While overall rate of BPAR including borderlines were similar (B: 17.4 % versus A: 16.1 % (see Figure 2), a statistically significant difference of higher than borderline graded BPAR was noted (B: 11.6 % vs. A: 5.2 %; p = 0.027). Safety parameters such as delayed graft function, kidney function, infections or post-transplantation diabetes mellitus did not differ. Conclusion An initial fixed low prolonged release tacrolimus dose of 5 mg/day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. (EudraCT-Nr: 2013-001770-19).