Ethnic differences in the population pharmacokinetics and pharmacodynamics of warfarin
Ethnic differences in the population pharmacokinetics and pharmacodynamics of warfarin
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DOI：
10.1007/s10928-009-9138-4
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发表时间：
2010-02-01
影响因子：
2.5
通讯作者：
Aarons, Leon
中科院分区：
文献类型：
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作者：
Yuen, Eunice;Gueorguieva, Ivelina;Aarons, Leon
新加坡的三个主要亚洲民族(华人、马来人和印度人)之间记录了华法林维持剂量的种族差异。研究表明，细胞色素P450 2C9(细胞色素P450 2C9)基因多态性本身并不能完全解释这些差异。最近的报告表明，VKORC1(维生素K环氧化物还原酶亚单位)单倍型更能预测华法林的疗效。采用群体药代动力学/药效学(PK/PD)模型技术，对16名中国和印度受试者单剂量服用华法林25 mg后的PK和PD进行了研究。为了进一步研究华法林反应的潜在差异，尝试了一种结合维生素K循环的半机械建模方法(使用对PCA活性的间接反应模型)，使用带有贝叶斯推理的总体方法。所有8名印度受试者都具有H7H7 VKORC1单倍型，3名印度受试者携带*2/wt或*3/wt CYP2C9基因。6名中国受试者携带H1H1 VKORC1单倍型，1名携带H1H7基因。所有中国受试者均为纯合子(wt/wt)。对稳态进行模拟，以检测具有不同CYP2C9和VKORC1基因多态的受试者的华法林反应。单个*2或*3等位基因的存在使S-华法林平均清除量从0.276(0.04)降低到0.180(0.11)L/小时，下降了35%。在H7H7单倍型受试者中，具有H7H7单倍型的受试者平均(SE)C-50，C-S(达到最大疗效50%所需的C-S浓度)从H1H1组的206(6.7)ng/ml增加到479(7.3)。在H1H7单倍型受试者中，平均值(SE)C-50、C-S较H1H1单倍型受试者增加1.4倍至288(1.3)ng/ml。稳态模拟表明，虽然CYP2C9基因多态影响华法林的PK，但VKORC1单倍型可能是华法林反应的更好预测因子。由于本研究中90%的中国受试者和100%的印度受试者具有VKORC1H1单倍型，因此本研究中华法林反应的种族差异似乎与VKORC1单倍型的差异有关。
Ethnic differences in warfarin maintenance doses have been documented amongst the three major Asian ethnic groups (Chinese, Malay and Indian) in Singapore. Studies have shown that cytochrome P450 2C9 (CYP2C9) polymorphisms alone did not entirely account for these differences. Recent reports suggest that VKORC1 (subunit of vitamin K epoxide reductase) haplotypes are more predictive of warfarin response. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling techniques were employed to characterise the PK and PD of warfarin in a healthy volunteer study of 16 Chinese and Indian subjects following a single 25 mg dose of warfarin. To further investigate the underlying differences in warfarin response, a semi-mechanistic modelling approach (using an indirect response model for PCA activity) incorporating the vitamin K cycle was attempted using population methods with Bayesian inference. All eight Indian subjects had H7H7 VKORC1 haplotypes and three had either *2/wt or *3/wt CYP2C9 genotypes. Six Chinese subjects had H1H1 VKORC1 haplotypes and one had H1H7. All Chinese subjects were homozygous wt/wt for CYP2C9. Simulations to steady state were performed to examine warfarin response in subjects with different CYP2C9 and VKORC1 polymorphisms. The presence of a single *2 or *3 CYP2C9 allele reduced mean [SE (standard error)] S-warfarin clearance by 35% from 0.276 (0.04) to 0.180 (0.11) l/h. Subjects with VKORC1 haplotype groups of H7H7 hadincreased mean (SE) C-50,C-S (concentration of S-warfarin required to achieve 50% of maximum effect) of 479 (7.3) compared to 206 (6.7) ng/ml in subjects with the H1H1 groups. For subjects with the H1H7 haplotype, mean (SE) C-50,C-S increased 1.4 times to 288 (1.3) ng/ml compared to subjects with H1H1 haplotypes. Steady state simulations showed that whilst CYP2C9 polymorphisms affect the PK of warfarin, VKORC1 haplotypes may be better predictors of warfarin response. Since 90% of Chinese subjects had the VKORC1 H1 haplotype and 100% of Indian subjects the H7 haplotype in this study, ethnic differences in warfarin response in this study appear to be linked to differences in VKORC1 haplotypes.