title: Population pharmacokinetic analysis of tacrolimus in Mexican paediatric renal transplant patients: role of CYP3A5 genotype and formulation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: Carlos Orlando
authors.initials: CO
authors.lastname: Jacobo-Cabral
authors.affiliation: Nephrology Research Laboratory, Federico Gómez Children's Hospital of Mexico, Mexico City, Mexico.
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Roca
authors.affiliation: Department of Pharmacobiology, University of Guadalajara, Guadalajara, Mexico.
authors.forename: Elba Margarita
authors.initials: EM
authors.lastname: Romero-Tejeda
authors.affiliation: Nephrology Research Laboratory, Federico Gómez Children's Hospital of Mexico, Mexico City, Mexico.
authors.forename: Herlinda
authors.initials: H
authors.lastname: Reyes
authors.affiliation: Nephrology Research Laboratory, Federico Gómez Children's Hospital of Mexico, Mexico City, Mexico.|Department of Pharmacology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.
authors.forename: Mara
authors.initials: M
authors.lastname: Medeiros
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castañeda-Hernández
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain.|IdiSNA Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000293:Adolescent; D002626:Chemistry, Pharmaceutical; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008800:Mexico; D008954:Models, Biological; D010597:Pharmacogenetics; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CYP3A5; formulation; paediatric; population pharmacokinetics; renal transplant; tacrolimus
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