Explaining variability in ciclosporin exposure in adult kidney transplant recipients.
Explaining variability in ciclosporin exposure in adult kidney transplant recipients.
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DOI：
10.1007/s00228-010-0810-9
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发表时间：
2010-06
影响因子：
2.9
通讯作者：
Guchelaar, Henk-Jan
中科院分区：
文献类型：
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作者：
Press, Rogier R.;Ploeger, Bart A.;den Hartigh, Jan;van der Straaten, T.;van Pelt, Hans;Danhof, Meindert;de Fijter, Hans;Guchelaar, Henk-Jan
由于环孢素A（CsA）药代动力学的变异性，肾移植受者的最佳CsA暴露量难以达到。更好地了解CsA暴露的变异性可能是个体化治疗的好方法。具体而言，CsA代谢相关基因的遗传变异性可以解释暴露差异。因此，本研究旨在确定遗传多态性和CsA暴露的变异性之间的关系，同时考虑变异性的非遗传来源。初治肾移植患者（n = 33）接受CsA治疗1年，并在全年多次进行广泛的血液采样。非遗传协变量血细胞比容、血清白蛋白浓度、胆固醇、人口统计学（即，采用非线性混合效应模型研究了体重、CsA给药间隔、泼尼松龙剂量和ABCB 1、CYP 3A 4、CYP 3A 5和PXR基因多态性对CsA药代动力学的影响。CsA的药代动力学符合延迟吸收的二室模型。体重被确定为最重要的协变量，并解释了CsA清除率随机个体间变异性的35%。此外，以20 mg/天或更高剂量同时使用泼尼松龙与CsA清除率高22%相关，因此CsA暴露量较低。相比之下，没有相当大的基因型效应（即，大于30-50%）。看来，选择的遗传标记解释CsA暴露的变异性不足以成为临床相关性。因此，在根据体重给予个体化剂量后，仍然需要进行治疗药物监测，以优化CsA暴露，并且如本研究所示，与泼尼松龙联合给药。
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. 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. 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. 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.
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影响因子：
6.7
作者：
HEBERT, MF;ROBERTS, JP;BENET, LZ
通讯作者：
BENET, LZ
影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
2.9
作者：
AWEEKA, FT;TOMLANOVICH, SJ;BENET, LZ
通讯作者：
BENET, LZ
DOI：
10.1007/bf01062270
发表时间：
1990-08-01
期刊：
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS
影响因子：
--
作者：
KARLSSON, MO;LINDBERGFREIJS, A
通讯作者：
LINDBERGFREIJS, A
影响因子：
3.3
作者：
Konishi, H;Sumi, M;Yamaji, A
通讯作者：
Yamaji, A