Background

Tacrolimus is available as twice-daily (TAC-BID) and once-daily (TAC-QD) formulations. Findings from pharmacokinetic and short-term trials are available. However, results from long-term trials are limited.We conducted a 5-year randomized trial to determine whether TAC-QD would be noninferior to TAC-BID regarding graft failure (non-censored for death), biopsy-proven rejection, nephrotoxicity, complications, and allograft function.

Subjects and Methods

De novo living transplant candidates were randomly assigned to TAC-QD (n=62) or TAC-BID (n=63). TAC was initiated 7 days pre-operatively at 0.10 mg/kg/day. The dose was adjusted to maintain a trough level of 7–9 ng/mL for 1 or 2 months and 4–7 ng/mL thereafter. Patients were given mycophenolate mofetil and methylprednisolone concomitantly with antibody induction.Non-inferiority margin was 10% risk difference.

Results

The 5-year cumulative graft failure rates were 6.5% and 9.5% in the TAC-QD and TAC-BID groups, respectively. The hazard ratio (HR) of the TAC-QD group was 0.66 (95% CI: 0.19-2.33, P=0.515). The upper limit of the 95% CI had to be less than the pre-specified inferiority margin of 10% and noninferiority of TAC-QD was conclusive (non-inferiority test: P=0.009). The 5-year biopsy-proven acute rejection rates were 30.7% and 32.0% in the TAC-QD and TAC-BID groups, respectively. The TAC-QD group had an HR of 0.99 (95% CI: 0.53-1.85, P=0.966), and the noninferiority of TAC-QD inthroughout period was slightly inclusive (noninferiority test: P=0.09). Within post-transplant 3 months, TAC-QD had an unfavorable HR of 1.87 (95% CI: 0.63-5.58, P=0.262). Conversely, subsequent period HR in TAC-QD was favorable effect (HR: 0.69, 95% CI: 0.31-1.54, P=0.367). The rate of nephrotoxicity tended to be lower in KTRs who were allocated TAC-QD than in those who were administered TAQ-BID (P=0.072). There were no differences in serum creatinine and eGFR levels between the two groups. TAC-QD was not inferior to TAC-BID regarding serum creatinine (noninferiority test: P<0.001) or eGFR (noninferiority test: P<0.001).

Conclusion

In a 5-year randomized noninferiority trial involving adult KTRs who underwent de novo living KT, we demonstrated that TAC-QD was not inferior to TAC-BID in terms of effectiveness, safety, and tolerability.

CITATION INFORMATION: Kakuta Y., Okumi M., Unagami K., Furusawa M., Ishida H., Tanabe K. Once-Daily versus Twice-Daily Tacrolimus in De Novo Living Kidney Transplantation Patients: A Multicenter, Parallel Group, Open-Label, 5-Year Randomized Noninferiority Trial Am J Transplant. 2017;17 (suppl 3).

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