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

Abstract

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 ng·h/mL/mg for Limustin(®) and Prograf(®), whereas in non-expressers, dose-normalized AUC was 54.4 ± 49.1 and 110.4 ± 42.9 ng·h/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.

Limited sampling strategy to predict the area under the curve of tacrolimus in Mexican renal transplant pediatric patients receiving Prograf® or non‐innovator formulations

“…A list of tacrolimus brand names worldwide is currently counting 258 products, all formulations included . Part of the transplant community has been, and still is, concerned that the PK properties of generic tacrolimus formulations may be different from those of the innovator product . It has been reported that substandard tacrolimus formulations are presently commercialized in Mexico and other emerging countries.…”

“…It has been reported that non‐innovator formulations from several emerging not highly regulated, countries, including Mexico, do not meet the quality criteria established for the innovator, including the dissolution profile . Moreover, previous studies from our research group have shown that some low‐quality tacrolimus formulations result in a lower bioavailability in children . Hence, if an LSS is going to be implemented for pediatric patients, including those from emerging countries, its ability to predict the tacrolimus AUC in all available formulations is of crucial importance.…”

Dosing recommendations based on population pharmacokinetics of tacrolimus in Mexican adult patients with kidney transplant

“…is susceptible to formulation manufacturing, affecting drug delivery and bioavailability . An investigation by Jacobo‐Cabral et al indicated that Limustin ® has a lower bioavailability when compared to an innovator product (Prograf ® ); moreover, Petan et al demonstrated that Framebin ® showed slower and incomplete drug dissolution, as well as low solubility, and the content varied widely when compared to the innovator product (Prograf ® ). For these reasons, it was decided that generic formulations, administered to patients included in the present study, had to be classified based on corresponding blood trough concentrations corrected by dose of tacrolimus to determine the relative bioavailability among generic formulations.…”

Appreciating the need for greater understanding of the pharmacokinetics of drugs in children and adolescents

“…Instead, children make hydroxylated metabolites which result in dramatic changes in the sirolimus half‐life from 7 hours in a preschool child to 72 hours in adults . Even when switching formulations of the same drug, there may be substantial variability which may lead to over‐ or underimmunosuppression . For tacrolimus, it is known that there is a biphasic change with age and bone maturation.…”