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 |
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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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