Genetic Polymorphisms and the Impact of a Higher Clopidogrel Dose Regimen on Active Metabolite Exposure and Antiplatelet Response in Healthy Subjects
Genetic Polymorphisms and the Impact of a Higher Clopidogrel Dose Regimen on Active Metabolite Exposure and Antiplatelet Response in Healthy Subjects
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DOI：
10.1038/clpt.2011.127
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发表时间：
2011-08-01
影响因子：
6.7
通讯作者：
Dubar, M.
中科院分区：
文献类型：
--
作者：
Simon, T.;Bhatt, D. L.;Dubar, M.
在四个 CYP2C19 基因型定义的代谢者组中进行了双盲交叉研究，以评估增加氯吡格雷剂量是否可以克服 CYP2C19 弱代谢者 (PM) 药效学反应降低的问题。四个代谢组中每组的 10 名健康受试者被随机接受氯吡格雷治疗方案，即 300 毫克负荷剂量 (LD) 和 75 毫克/天维持剂量 (MD)，为期 4 天，然后是 600 毫克 LD 和 150 毫克/天 MD，反之亦然。与粗代谢者 (EM) 中的相应暴露水平相比，75 毫克/天方案中氯吡格雷活性代谢物 H4 (clopi-H4) 的暴露水平在 PM 中降低了 71%，在 150 毫克/天方案中降低了 64%。在 PM 中，二磷酸腺苷 (ADP) 5 μmol/l 诱导的最大血小板聚集 (MPA) 比 EM 中的相应值在 75 mg/天方案中降低了 10.5%，在 150 mg/天方案中降低了 7.9%。接受氯吡格雷 600 毫克 LD/150 毫克/天 MD 方案的 PM 的 clopi-H4 暴露和 MPA 水平与接受 300 毫克 LD/75 毫克/天 MD 方案的 EM 相似。在评估 CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP3A5、CYP2D6、ABCB1 和 P2RY12 多态性（N = 396 名健康受试者）的汇总分析中，只有 CYP2C19 对抗血小板反应有显着影响。在健康的 CYP2C19 PM 中，根据 MPA 水平评估，600 mg LD/150 mg/天 MD 的氯吡格雷方案在很大程度上克服了 clopi-H4 暴露和抗血小板反应的减少。
A double-blind crossover study was conducted in four CYP2C19 genotype-defined metabolizer groups to assess whether increase in clopidogrel dosing can overcome reduced pharmacodynamic response in CYP2C19 poor metabolizers (PMs). Ten healthy subjects in each of four metabolizer groups were randomized to a clopidogrel regimen of a 300-mg loading dose (LD) and a 75-mg/day maintenance dose (MD) for 4 days followed by 600-mg LD and 150 mg/day MD, or vice versa. The exposure levels of clopidogrel's active metabolite H4 (clopi-H4) in PMs were 71% lower on the 75-mg/day regimen and 64% lower on the 150-mg/day regimen than the corresponding exposure levels in extensive metabolizers (EMs). In PMs, the maximal platelet aggregation (MPA) induced by adenosine diphosphate (ADP) 5 mu mol/l was 10.5% lower on the 75-mg/day regimen and 7.9% lower on the 150-mg/day regimen than the corresponding values in EMs. PMs who were on the clopidogrel regimen of 600-mg LD/150 mg/day MD showed clopi-H4 exposure and MPA levels similar to those in EMs who were on the regimen of 300-mg LD/75 mg/day MD. In a pooled analysis evaluating CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms (N = 396 healthy subjects), only CYP2C19 had a significant impact on antiplatelet response. In healthy CYP2C19 PMs, a clopidogrel regimen of 600-mg LD/150 mg/day MD largely overcomes diminished clopi-H4 exposure and antiplatelet response, as assessed by MPA levels.