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Explaining variability in ciclosporin exposure in adult kidney transplant recipients
Rogier R Press1, Bart A Ploeger, Jan den Hartigh
1Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. r.r.press@lumc.nl
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.
Insights
Genetic factors do not significantly impact ciclosporin A (CsA) levels in kidney transplant patients. Body weight and prednisolone dosage are key to optimizing CsA therapy, necessitating continued therapeutic drug monitoring.
Area of Science:
- Pharmacology
- Transplantation
- Genetics
Background:
- Ciclosporin A (CsA) pharmacokinetics exhibit significant inter-individual variability, complicating optimal exposure in kidney transplant recipients.
- Understanding sources of variability, including genetic factors, is crucial for personalized therapy.
- Genetic polymorphisms in drug-metabolizing enzymes and transporters may influence CsA exposure.
Purpose of the Study:
- To investigate the relationship between genetic polymorphisms in ABCB1, CYP3A4, CYP3A5, and PXR and CsA exposure variability.
- To identify non-genetic factors contributing to CsA pharmacokinetic variability in kidney transplant patients.
- To determine if genetic markers can adequately explain CsA exposure differences for clinical use.
Main Methods:
- A cohort of 33 de novo kidney transplant patients received CsA for one year.
- Extensive blood sampling and non-linear mixed-effects modeling were used to analyze CsA pharmacokinetics.
- Covariates included hematocrit, albumin, cholesterol, body weight, CsA dose interval, prednisolone dose, and genetic polymorphisms.
Main Results:
- Body weight was the primary covariate, explaining 35% of inter-individual variability in CsA clearance.
- Concurrent prednisolone use (≥20 mg/day) increased CsA clearance by 22%, leading to lower exposure.
- No significant genotype effects on CsA clearance were observed for the selected genes.
Conclusions:
- Selected genetic markers do not sufficiently explain CsA exposure variability for clinical relevance.
- Individualized dosing based on body weight and concurrent prednisolone use is recommended.
- Therapeutic drug monitoring remains essential for optimizing CsA exposure in kidney transplant recipients.
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