title: 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.
authors.affiliation: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, DF, Mexico.
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Jacobo-Cabral
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Roca
authors.forename: Herlinda
authors.initials: H
authors.lastname: Reyes
authors.forename: Lucero
authors.initials: L
authors.lastname: Lozada-Rojas
authors.forename: Leticia
authors.initials: L
authors.lastname: Cruz-Antonio
authors.forename: Mara
authors.initials: M
authors.lastname: Medeiros
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castañeda-Hernandez
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D019540:Area Under Curve; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016030:Kidney Transplantation; D008297:Male; D008800:Mexico; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D016559:Tacrolimus / Q000008:administration & dosage*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: bioavailability; bioequivalence; pediatric; renal transplant; tacrolimus