A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy
A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy
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DOI：
10.1038/sj.clpt.6100084
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发表时间：
2007-04-01
影响因子：
6.7
通讯作者：
Jonsson, E. N.
中科院分区：
文献类型：
--
作者：
Hamberg, A-K;Dahl, M-L;Jonsson, E. N.
这项研究的目的是描述华法林浓度和国际标准化比率(INR)反应之间的关系，并确定对剂量个体化重要的预测因素。采用S和R-华法林血药浓度、INR、细胞色素P450受体C9和VKORC1型在NONMEM中建立群体药代动力学/药效学模型。抗凝反应符合抑制性E-MAX模型，S-华法林浓度是反应的唯一暴露预测因子。暴露和反应之间的延迟由具有两个平行的运输隔室链的运输隔室模型来解释。C9基因和年龄是S-华法林清除量的预测因子，VKORC1型是华法林敏感性的预测因子。预测的INR曲线显示了具有不同协变量集的患者之间重要的稳态差异；仅从早期INR评估无法预见的差异。为了提高华法林治疗的先验和后验个体化，重要的是要考虑到CYP2C9和VKORC1的基因型别和年龄。
The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E-MAX model, with S- warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S- warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.