Population pharmacokinetic analysis of tacrolimus in Mexican paediatric renal transplant patients: role of CYP3A5 genotype and formulation

Abstract

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.

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

“…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. This resulted in a higher bioavailability of Framebin ® than Limustin ® , demonstrating that generic formulations of tacrolimus are not interchangeable and switching between them will result in significant changes in blood concentrations; therefore, critical clinical attention and therapeutic monitoring are required …”

Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities?

“…In only 13.8% of the studies (N = 4), CYP3A5*3 variants were categorized into 3 groups: CYP3A5*1*1, *1*3, and *3*3, which were defined as extensive, intermediate, and poor metabolizers. 37,47,48,58 The fractional change in the average tacrolimus clearance was 1.39 (range 1.18-1.69) for intermediate and 1.8 (range 1.25-2.0) for extensive metabolizers compared to that of poor metabolizers. Across all the studies that investigated the CYP3A5*3 variant, the frequencies of the wild-type *1*1, heterozygous *1*3, and homozygous *3*3 were not equal.…”

“…16,32,33 With increased use of tacrolimus minimization protocols, newer immunoassays such as chemiluminescent microparticle immunoassay (N = 10) were introduced and provided improved sensitivity to less than 1 ng/mL with enhanced specificity. [34][35][36][37][38][39][40] In the remaining studies (ß30%), the assays conducted used a liquid chromatographic method coupled with mass spectrometry, which provides lower sensitivity and improved specificity but has limited availability at many centers ( Figure 2E). Assay methodology was not found to be a significant covariate.…”

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

“…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.…”