Explaining variability in ciclosporin exposure in adult kidney transplant recipients

Autor: Hans de Fijter, Bart A. Ploeger, Meindert Danhof, T. van der Straaten, Henk-Jan Guchelaar, Hans van Pelt, Jan den Hartigh, Rogier R. Press
Rok vydání: 2010
Předmět:
Adult
Male
Receptors
Steroid
ATP Binding Cassette Transporter
Subfamily B
Genotype
Prednisolone
Ciclosporin A Therapeutic drug monitoring Population pharmacokinetics Pharmacogenetics pregnane-x-receptor calcineurin inhibitors intravenous methylprednisolone clinical pharmacokinetics immunosuppressive drugs renal-transplantation genetic polymorphisms organ-transplantation oral bioavailability abcb1 polymorphisms
Physiology
Therapeutic drug monitoring
Biology
Drug Administration Schedule
Pharmacokinetics
Fluorescence Polarization Immunoassay
medicine
Cytochrome P-450 CYP3A
Humans
Pharmacology (medical)
Population pharmacokinetics
ATP Binding Cassette Transporter
Subfamily B
Member 1
Genetic variability
Kidney transplantation
Survival analysis
Aged
Pharmacology
Polymorphism
Genetic
medicine.diagnostic_test
Body Weight
Pregnane X Receptor
General Medicine
Middle Aged
Ciclosporin
medicine.disease
Kidney Transplantation
Survival Analysis
Pharmacogenetics
Immunology
Cyclosporine
Female
Ciclosporin A
Immunosuppressive Agents
medicine.drug
Zdroj: European Journal of Clinical Pharmacology, 66(6), 579-590
European Journal of Clinical Pharmacology
ISSN: 1432-1041
0031-6970
Popis: Purpose Optimal ciclosporin A (CsA) exposure in kidney transplant recipients is difficult to attain because of variability in CsA pharmacokinetics. A better understanding of the variability in CsA exposure could be a good means of individualizing therapy. Specifically, genetic variability in genes involved in CsA metabolism could explain exposure differences. Therefore, this study is aimed at identifying a relationship between genetic polymorphisms and the variability in CsA exposure, while accounting for non-genetic sources of variability. Methods De novo kidney transplant patients (n = 33) were treated with CsA for 1 year and extensive blood sampling was performed on multiple occasions throughout the year. The effects of the non-genetic covariates hematocrit, serum albumin concentration, cholesterol, demographics (i.e., body weight), CsA dose interval, prednisolone dose and genetic polymorphisms in genes encoding ABCB1, CYP3A4, CYP3A5, and PXR on CsA pharmacokinetics were studied using non-linear mixed effect modeling. Results The pharmacokinetics of CsA were described by a two-compartment disposition model with delayed absorption. Body weight was identified as the most important covariate and explained 35% of the random inter-individual variability in CsA clearance. Moreover, concurrent prednisolone use at a dosage of 20 mg/day or higher was associated with a 22% higher clearance of CsA, hence lower CsA exposure. In contrast, no considerable genotype effects (i.e., greater than 30–50%) on CsA clearance were found for the selected genes. Conclusions It appears that the selected genetic markers explain variability in CsA exposure insufficiently to be of clinical relevance. Therefore, therapeutic drug monitoring is still required to optimize CsA exposure after administration of individualized doses based on body weight and, as this study suggests, co-administration of prednisolone.
Databáze: OpenAIRE
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