Bioequivalence of Generic Tacrolimus (Tacrobell®) to Prograf® in De Novo Renal Transplant Patients

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Introduction: Bioequivalence of the generic tacrolimus formulation to the reference product has been demonstrated in healthy subjects. However, bioequivalence should be demonstrated in solid organ transplant patients who have difference clearance and half life of tacrolimus compared with healthy volunteers. The steady-state bioequivalence in prevalent transplant patient is also important. Methods: This single-center, open-label, two period, crossover, prospective, randomized study was conducted at the Seoul National University Hospital (NCT01055964). This study prospectively compared the clinical efficacy, safety and pharmacokinetic profile between Prograf® (Astellas Pharma, Tokyo, Japan) and generic tacrolimus (Tacrobell®; Chong Kun Dang Pharmaceutical Corp., Seoul, Korea) after approval by the Institutional Review Board of the Seoul National University Hospital (IRB No. H-0805-032-242). Results: A total of 126 de novo renal transplant patients were enrolled in this study. There was no difference in demographic characteristics between Tacrobell group (N=63) and Prograf group (N=63). All patients received triple immunosuppressive therapy including tacrolimus, mycophenolate mofetil and steroids. Although Tacrobell group had a tendency of higher acute rejection rate (18.5% vs. 7.9%, P=0.08), Tacrobell group showed equivalent graft (100% vs. 96.8%) and patient (100% vs. 98.4%) survival, biopsy-confirmed calcineurin inhibitor toxicity (5.8% vs. 4.7%) and comparable renal function (P>0.05 up to 6 months) compared to Prograf group within the 6 month after transplantation. Two patients in Tacrobell group suffered from major adverse events including renal dysfunction related with FK toxicity (n=1) and drug-induced hepatotoxicity (n=1). There was no difference in the incidence rate of minor adverse events. The pharmacokinetics of tacrolimus were evaluated on day 10 (54 in Tacrobell group and 63 in Prograf group) and 6 months (38 in Tacrobell group and 55 in Prograf group) after transplantation. On day 10, Tacrobell group showed comparable C0 (9.8±2.5 vs 9.7±3.0, P=0.80) but significantly higher Cmax (35.1±14.5 vs. 23.4±9.1, P< 0.001), shorter Tmax (1.0±0.5 vs. 1.4±0.8, P=0.002) and lower AUC0-12 (164.0±44.4 vs. 147.9±43.8, P=0.05) compared to Prograf group (Figure 1). This pharmacokinetic pattern of ‘early and high Cmax with rapid wash-out’ in Tacrobell group abated with time, and Tacrobell group showed equivalent Cmax (19.6±9.5 vs. 19.6±7.4, P=0.99), Tmax (1.3±0.9 vs. 1.5±1.1, P=0.31) and AUC0-12 (106.8±34.7 vs.118.5±34.2, P=0.11) with slightly lower C0 (5.7±1.6 vs. 6.9±2.2, P=0.004) on 6 month after transplantation. Sixty nine conversions were carried out at 6 month and 9-month pharmacokientics were evaluated in 66 patients (27 in Tacrobell group and 39 in Prograf group). The Tacrobell group (conversion to Prograf) showed significantly decreased Cmax (15.6±5.7 from 18.8±7.5, P=0.03) and AUC0-12 (95.8±24.4 from 105.4±24.8, P=0.046) compared with 6 month PK profile while the Prograf group (conversion to Tacrobell) had a tendency of higher Cmax (23.1±12.2 from 19.7±7.4, P=0.112), lower C0 (6.0±1.9 from 6.6±1.9, P=0.09) and equivalent AUC0-12 (112.5±35.4 from 116.3±32.4, P=0.58). Conclusions: The Tacrolimus generic product (Tacrobell®) can be safely used in de novo renal transplant patients and the transplant patients currently taking the reference tacrolimus formulation can be safely switched to Tacrobell® provided transplant clinicians know the pharmacokinetic characteristics of two tacrolimus formulations.