ST LOUIS (MD Consult) - On March 12, 2010, the US Food and Drug Administration (FDA) issued a notice that a Boxed Warning has been added to the label for the platelet inhibitor Plavix (clopidogrel). This warning alerts health care professionals that certain patients may lack the ability to properly metabolize the drug and thus do not effectively convert Plavix to its active form in the body. In these patients, Plavix has a reduced effect on platelets, thereby reducing the drug's ability to prevent myocardial infarction, stroke, and cardiovascular death.

In May 2009, the FDA added information about poor metabolizers of Plavix to the drug label. The decision to more prominently highlight this information by the addition of a Boxed Warning came after the agency conducted a review of additional data. The FDA recommends that health care professionals consider use of other antiplatelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

The liver enzyme CYP2C19 is primarily responsible for the formation of the active metabolite of Plavix. Pharmacokinetic and antiplatelet tests of the active metabolite of Plavix show that the drug levels and antiplatelet effects differ depending on a patient's genotype of the CYP2C19 enzyme. The following represent the different alleles of CYP2C19 that compose a patient's genotype:

 

·         The CYP2C19*1 allele has fully functional metabolism of Plavix.

·         The CYP2C19*2 and *3 alleles have no functional metabolism of Plavix. These two alleles account for most of the reduced-function alleles in patients who are white (85%) or of Asian descent (99%) who are classified as poor metabolizers.

·         The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Plavix but are seen less frequently than the CYP2C19*2 and *3 alleles.

 

A patient with 2 loss-of-function alleles (as defined above) will have poor metabolizer status. It is estimated that 2% to 14% of the population fall into this category.

 

Tests are available to identify genetic differences in CYP2C19 function. Health care professionals are being advised to consider use of other antiplatelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

 

A higher-dose regimen of Plavix (600 mg loading dose followed by 150 mg once daily) has been shown to increase the antiplatelet response in poor metabolizers. However, an appropriate dose regimen for poor metabolizers has not been established in a clinical outcome trial.

 

圣路易斯(MD Consult)——2010年3月12日，美国食品药品管理局(FDA)发布了一则通告，内容为血小板抑制剂Plavix (氯吡格雷)的说明书中增加了一个黑框警告。该警告提醒医护人员，某些患者可能缺乏对该药的正常代谢能力，因此在体内无法将Plavix有效地转化成其活性形式。对于这部分患者，Plavix对血小板的效应降低，因此降低了预防心肌梗死、卒中以及心血管死亡的效力。

 

2009年5月，FDA在该药的说明书中增加了有关Plavix弱代谢者的信息。FDA在对新增的数据进行审查后，决定增加一个黑框警告，突显上述信息。FDA建议医护人员，对查出是Plavix弱代谢者的患者应考虑使用其他抗血小板药物，或实施替代给药策略。

肝酶CYP2C19是将Plavix转化成活性代谢产物的主要酶。Plavix活性代谢产物的药代动力学和抗血小板试验显示，该药的水平和抗血小板效应因患者CYP2C19 酶的基因型不同而异。以下是构成患者CYP2C19酶基因型的不同等位基因：

 

·         CYP2C19m1等位基因具有足够的代谢Plavix的功能。

·         CYP2C19m2和m3等位基因对Plavix无代谢功能。这两个等位基因是导致大多数归为弱代谢者的白种人(85%)或亚裔美国人(99%)对该药的代谢功能降低的原因。

·         CYP2C19m4、m5、m6、m7和m8，以及其他等位基因可能与对Plavix代谢缺如或降低有关，但相对于CYP2C19m2 和m3等位基因较不常见。

 

存在2个功能缺失等位基因(如上文所述)的患者会有代谢不良的情况。据估计，该群体中有2%~14%会属于这种情况。

目前有检查CYP2C19功能基因差异的试验。FDA建议医护人员对归为弱代谢者的患者应考虑使用其他抗血小板药或实施替代给药策略。

有研究表明，对弱代谢者采用较高剂量的Plavix给药方案(600 mg 负荷剂量，继以150 mg，1次/天)可增加抗血小板效应。然而，针对弱代谢者的合理给药方案尚未在临床转归试验中予以证实。