A New CYP3A53 and CYP3A422 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach

Background Single nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes have been reported to be an important cause of variability in the pharmacokinetics of tacrolimus in renal transplant patients. The aim of this study was to merge all of the new genetic information available with tacroli...

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Bibliographic Details
Published in:Clinical pharmacokinetics 2017-08, Vol.56 (8), p.963-975
Main Authors: Andreu, Franc, Colom, Helena, Elens, Laure, van Gelder, Teun, van Schaik, Ronald H. N., Hesselink, Dennis A., Bestard, Oriol, Torras, Joan, Cruzado, Josep M., Grinyó, Josep M., Lloberas, Nuria
Format: Article
Language:English
Subjects:
Adolescent
Adult
Age
Aged
Aged, 80 and over
Cytochrome P-450 CYP3A - genetics
Drug dosages
Female
Genotype
Genotype & phenotype
Glycoproteins
Health risk assessment
Hematocrit - methods
Humans
Immunosuppressive Agents - blood
Immunosuppressive Agents - pharmacokinetics
Immunosuppressive Agents - therapeutic use
Internal Medicine
Kidney Transplantation - statistics & numerical data
Male
Medicine
Medicine & Public Health
Metabolism
Middle Aged
Models, Theoretical
Original Research Article
Pharmacology/Toxicology
Pharmacotherapy
Polymorphism, Single Nucleotide - genetics
Population
Predictive Value of Tests
Prospective Studies
Retrospective Studies
Tacrolimus - blood
Tacrolimus - pharmacokinetics
Tacrolimus - therapeutic use
Transplant Recipients - statistics & numerical data
Transplants & implants
Young Adult
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Description
Summary:Background Single nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes have been reported to be an important cause of variability in the pharmacokinetics of tacrolimus in renal transplant patients. The aim of this study was to merge all of the new genetic information available with tacrolimus pharmacokinetics to generate a more robust population model with data from renal transplant recipients. Methods Tacrolimus exposure data from 304 renal transplant recipients were collected throughout the first year after transplantation and were simultaneously analyzed with a population pharmacokinetic approach using NONMEM ® version 7.2. Results The tacrolimus whole-blood concentration versus time data were best described by a two-open-compartment model with inter-occasion variability assigned to plasma clearance. The following factors led to the final model, which significantly decreased the minimum objective function value ( p  
ISSN:0312-5963
1179-1926
DOI:10.1007/s40262-016-0491-3