Recently, once-daily tacrolimus extended-release formulation (TACER) has been accepted in kidney transplantation, however its optimal dosing are not well evaluated. We have validated low dose (LD) and very low dose (VLD) TACER / MMF protocol in de novo kidney transplant recipients using limited sampling strategies to estimate tacrolimus exposure.

Patients and Methods: Fifty Living-donor kidney transplant recipients were prospectively randomized into two group, 1) LD group (n=26) ; targeting tacrolimus area under curve profiles (TAC-AUC) 0-24 by limited sampling strategy 250ng[bull]hr/ml during the first 1 months and reduced to 200ng[bull]hr/ml after 3 months. 2) VLD group (n=24); targeting TAC-AUC0-24 200ng[bull]hr/ml during the first 1 months and reduced to 150ng[bull]hr/ml after 3 months. All administered in combination with mycophenolate mofetile (MMF), corticosteroid and basiliximab induction. MMF was started with 1250mg BID and reduced to 750mg BID at 2 weeks after transplant, and adjusted to achieve MPA-AUC0-12 between 30-60 [mu]g[bull]hr/L. Subclinical rejection and CNI toxicity were evaluated by protocol biopsy after 1 and 12 months.

Results: With a mean observation of 18 months (6-35), patients and graft survival are 100% in both groups. Mean tacrolimus trough concentration at 1 month and 1 year after transplant was 5.5±1.8, 5.2±0.9 ng/ml in LD group, and 4.7±1.1, 3.2±0.7 ng/ml in VLD group. Significant difference in tacrolimus trough level was observed from 3 months to 1 year after transplant (p<0.05). Subclinical or clinical T cell mediated rejection were observed in 0% in LD group and 8.3% in VLD group, while incidence of CMV infection was reduced in VLD group (5.9%) compared to LD group (15.9%) respectively. CNI toxicity were observed in 7.7% in LD group and 12.5% in VLD group in 1month protocol biopsies, but those findings were alleviated in 1 year protocol biopsy (7.1% in LD and 6.3% in VLD group). Mean eGFR were equivalent between the two groups and maintained at 52.8±10.6ml/min/1.73m2 in LD group and 50.5±11.7ml/min/1.73m2 in VLD group at 1 year after transplant.

Conclusions: This study suggests that tacrolimus exposure with TACER combination with MMF can be safely reduced to very low level with reduced CMV infection rate and without significant increased rejection rate.

CITATION INFORMATION: Watarai Y, Okada M, Futamura K, Nagai T, Yamamoto T, Tsujita M, Hiramitsu T, Goto N, Narumi S, Kobayashi T. Comparison of Low Dose and Very Low Dose Extended-Release Tacrolimus / MMF in De Novo Kidney Transplant Recipients. Am J Transplant. 2016;16 (suppl 3).

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