A Retrospective Study on Effectiveness and Safety of the Novel Once-Daily Melt-Dose Tacrolimus in a Spanish Cohort of Stable Kidney Transplant Recipients Converted from Once or Twice-Daily Formulations

Abstract

The ReconocE study group. Background Tacrolimus (TAC) is currently included in most immunosuppressive protocols in kidney transplantation. Envarsus®, a new extended-release once-daily TAC formulation with an improved pharmacokinetic profile based on Melt-Dose technology, has become available recently. However, data on conversion between different TAC formulations obtained in routine clinical practice are lacking. The objective of this retrospective, non-interventional, multicenter study was to evaluate renal function, TAC trough levels (Cmin) and dosing, as well as safety parameters, following conversion from Prograf® or Advagraf® to Envarsus® in stable kidney transplant recipients. Patients and Methods The study was approved by the corresponding ethics committees. Stable adult kidney transplant recipients (>6 month after transplantation) with at least 3 months of post-conversion follow-up were included. Patients had been converted between December 2015 and October 2016. Demographic data, TAC Cmin, total daily dose (TDD), renal function (CKD-EPI) and biochemical parameters in the 3 months before conversion and 3 months after conversion were collected. The reference conversion ratio was 1:0.7, as recommended by Envarsus® SmPC. Results A total of 389 patients were included (62% males, mean age 56.6±13.6 years, 93.7% Caucasians). The mean time from transplant to conversion was 70.4 ± 63.1 months; the mean post-conversion follow-up was 8.4 months. 84.6% of the grafts were from deceased donors. Data from 365 patients were evaluated for effectiveness, and from 384 for safety analysis. There were no significant differences in TAC Cmin before and after conversion (7.4±2.5 ng/mL and 7.6±2.6 ng/mL respectively; p = 0.95). Mean TDD before and after the conversion was 4.3±3.3 mg and 3.1±2.3 mg respectively, a reduction of 28% (p<0.0001), reduction was larger in patients converted from Advagraf® (37%; n=197, p<0.0001). Melt-Dose technology enhanced TAC bioavailability by 34%. Mean eGFR (CPD-EPI) remained stable before and after conversion (52.3±21.3 and 51.5±21.6 ml/min/1,73m2, respectively; p=0.14). There were no significant differences in pre- and post-conversion laboratory parameters. None of the patients experienced treatment failure during the 3 month of follow-up. The mean number of post-conversion dose adjustments to maintain Cmin within target levels was 0.9±1.4. A total of 57 adverse reactions (AR), of them 4 serious were registered in 49 patients before conversion, and 11 AR (1 serious) in 10 patients after conversion. Neurotoxic side effects improved after conversion in 51.2% of patients. Conversion to Envarsus® was associated with a significant reduction in cost of TAC treatment. Conclusion In our real-life population, conversion to Envarsus® allowed for reducing TAC TDD by 28% while maintaining similar Cmin and renal function over 3 months after conversion. There were no episodes of graft rejection or new safety signals. In addition, the conversion was cost-effective.