Therapeutic equivalence and pharmacokinetics of generic tacrolimus formulation in <i>de novo</i> kidney transplant patients

Abstract

There is a growing concern about the therapeutic equivalence of the generic tacrolimus formulation (GEN Tacrolimus) to the reference tacrolimus (REF Tacrolimus) in solid organ transplantation. A prospective, randomized study of 126 de novo renal transplant patients was conducted to compare the efficacy, safety and pharmacokinetic (PK) profiles between GEN tacrolimus (n 63) and REF tacrolimus (n 63). The PK of tacrolimus was evaluated on Day 10 and 6 months under steady-state condition. Crossover study was carried out in 66 patients at 6 months. On Day 10, 117 patients completed PK profiles (54 GEN tacrolimus and 63 REF tacrolimus) and GEN tacrolimus showed comparable C-0 (9.8 2.5 versus 9.7 3.0 ng/mL, P 0.80) but significantly higher dose-normalized C-max (309.1 191.9 versus 192.5 95.2 ng/mL/mg/kg, P 0.001). The dose-normalized AUC(012) tended to be higher in the GEN tacrolimus than in the REF tacrolimus group (1513.4 935.4 versus 1262.5 593.5 ng.h/mL/mg/kg, P 0.084). Because of this early and high C-max with a rapid decline in GEN tacrolimus concentration, the trough concentration was maintained lower than that of REF tacrolimus. At 6 months, GEN tacrolimus showed equivalent dose-normalized AUC(012) (1882.2 935.6 versus 1718.1 946.3 ng.h/mL/mg/kg, P 0.429) but still higher dose-normalized C-max (346.3 184.4 versus 273.2 148.9 ng/mL/mg/kg, P 0.056), despite a reduced trough concentration (5.7 1.6 versus 6.9 2.2 ng/mL, P 0.004). PK profiles evaluated at 9 months showed that generic substitution also resulted in an early and high C-max. Efficacy and safety data were comparable over the 9-month study period. Therapeutic equivalence and the PK of GEN tacrolimus should be evaluated in patients undergoing de novo renal transplantation.