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Population pharmacokinetic analysis of tacrolimus in Mexican paediatric renal transplant patients: role of CYP3A5 genotype and formulation
Author(s) -
JacoboCabral Carlos Orlando,
GarcíaRoca Pilar,
RomeroTejeda Elba Margarita,
Reyes Herlinda,
Medeiros Mara,
CastañedaHernández Gilberto,
Trocóniz Iñaki F.
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12649
Subject(s) - tacrolimus , nonmem , population , pharmacokinetics , cyp3a5 , medicine , dosing , pharmacology , renal transplant , transplantation , genotype , chemistry , biochemistry , environmental health , gene
Aims The 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. Methods Population 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. Results Tacrolimus 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. Conclusions Population PK modelling of tacrolimus in paediatric renal transplant recipients identified the tacrolimus formulation type as a significant covariate affecting the blood concentrations and confirmed the previously reported significant effect of CYP3A5 genotype on CL/ F . It allowed the design of a proposed dosage based on the final model that is expected to help to improve tacrolimus dosing.