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AIMSThe aims of this study were (i) to develop a population pharmacokinetic (PK) model of tacrolimus in a Mexican renal transplant paediatric population (n = 53) and (ii) to test the influence of different covariates on its PK properties to facilitate dose individualization. METHODSPopulation PK and variability parameters were estimated from whole blood drug concentration profiles obtained at steady-state using the non-linear mixed effect modelling software NONMEM® Version 7.2. RESULTSTacrolimus PK profiles exhibited high inter-patient variability (IPV). A two compartment model with first order input and elimination described the tacrolimus PK profiles in the studied population. The relationship between CYP3A5 genotype and tacrolimus CL/F was included in the final model. CL/F in CYP3A5*1/*1 and *1/*3 carriers was approximately 2-and 1.5-fold higher than in CYP3A5*3/*3 carriers (non-expressers), respectively, and explained almost the entire IPV in CL/F. Other covariates retained in the final model were the tacrolimus dose and formulation type. Limustin® showed markedly lower concentrations than the rest of the formulations. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Tacrolimus is a highly effective and widely used to prevent organ rejection in transplant patients.• Several elements contribute to the high inter-patient variability on tacrolimus pharmacokinetics (PK) including demographics and biological factors as well as certain polymorphisms.• The influence of tacrolimus formulation (generic or innovator) on its PK has not been tested. WHAT THIS STUDY ADDS• This study presents a population PK model of tacrolimus that found significant effect of CYP3A5*3, formulation and dose of tacrolimus on some of its PK parameters.• An estimator of the tacrolimus dose was developed based on the individual estimates of the PK parameters obtained from the final population PK model in which differences between formulations were important.

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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.

The aim of the study was to evaluate the efficacy and safety of the conversion of MMF to EC-MPS in pediatric renal transplant recipients. We included 12 patients with stable graft function who were receiving MMF treatment. In the first visit, a complete medical examination was performed, which included a GSRS, a nine-point pharmacokinetic profile, samples for renal, liver and hematological tests and evaluation of IMPDH2 gene expression. The patients were transferred to an equimolar dose of EC-MPS. Two wk later, a clinical evaluation and blood collection, as in the first visit were performed. There was no change in serum creatinine, leukocyte count, serum albumin, or transaminase levels, but we found a statistically significant reduction of hemoglobin after conversion (13.2 +/- 1.6 g/dL with MMF vs. 12.5 +/- 1.3 g/dL when receiving EC-MPS). The GSRS total mean score was 16 +/- 12 with MMF vs. 8 +/- 5 with EC-MPA (p < 0.05). There was no statistically significant difference between formulations in the gene expression of IMPDH 2, in the AUC(0-12h) or in C(max). However, peak concentration occurred later with EC-MPS.