Limustin®, a non‐innovator tacrolimus formulation, yields reduced drug exposure in pediatric renal transplant recipients

The aim of this study was to evaluate the bioavailability of two oral tacrolimus formulations, the innovator Prograf and a formulation commercialized in Mexico with the brand name Limustin, in children. Stable Mexican pediatric renal transplant recipients received the product authorized by their social security provider, being either Prograf or Limustin. At steady state, blood samples were drawn and tacrolimus blood concentration against time curves was constructed. CYP3A5 genotype was also determined. There was no significant difference in dose or in trough concentrations between formulations. However, AUC and Cmax were significantly higher with Prograf. The lower tacrolimus bioavailability with Limustin was observed in both expressers and non-expressers of the functional CYP3A5 protein. Dose-normalized AUC values in expressers were 12.7 � 11.9 and 48.7 � 20.4 ngh/mL/mg for Limustin and Prograf, whereas in non-expressers, dose-normalized AUC was 54.4 � 49.1 and 110.4 � 42.9 ngh/mL/mg for Limustin and Prograf, respectively (p < 0.05). Pharmaceutical quality analysis showed that Limustin dissolution at 120 min was 31.1 � 6.2% while Prograf dissolution was 100 � 4.8%. Furthermore, the mean percentage of labeled amount of Limustin and Prograf was 91.0 � 3.1% and 100.0 � 0.7%, respectively. Hence, Limustin exhibits pharmaceutical characteristics dissimilar to the innovator that likely explain the reduced tacrolimus exposure in children. We consider Limustin is not adequate for pediatric use.