Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

Abstract

Acute coronary syndromes (ACS) remain life-threatening disorders that are associated with high morbidity and mortality. Dual-antiplatelet therapy with aspirin and clopidogrel has shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in response to clopidogrel treatment in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19 that affect clopidogrel’s pharmacokinetics. While FDA has issued a boxed warning for CYP2C19 poor metabolizers due to a potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug-drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability and how they are interrelated is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence clopidogrel’s pharmacokinetics and pharmacodynamics and how they mechanistically contribute to inter-individual differences in response to clopidogrel treatment.

Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke

“…The prevalence of clopidogrel resistance in our study population was approximately 36% (n=69), which is within the previously reported range [7,8] . Previous studies have shown that the antiplatelet effect of clopidogrel is achieved after taking a daily dose of 75 mg for 3 to 7 d [4,27] .…”

“…In fact, several clinical studies conducted in Chinese, Japanese and Korean patients reveal that the frequencies of clopidogrel resistance in Asians may vary from 20% to 65%, which highly exceeds the incidence reported in other ethnic groups [7,8] . The underlying mechanisms of clopidogrel resistance remain unknown.…”

“…The underlying mechanisms of clopidogrel resistance remain unknown. Previous studies indicate that genetic factors may greatly contribute to the variability of platelet activity [8] . Because clopidogrel is a prodrug that requires a two-step oxidation process for activation in the liver, polymorphisms of genes encoding the metabolic enzymes involved in clopidogrel biotransformation may be the primary influential factors of clopidogrel responsiveness.…”

Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention

“…Although the efficacy of clopidogrel is linked to several enzymes, transporters and acceptors, such as CYP2B6, CYP3A4, CYP3A5, ABCB1, PON1, and P2Y12, the most important factors suggested to be associated with low response to the drug are CYP2C19 * 2 and CYP2C19 * 3 variants (Nagashima et al, 2013; Jiang et al, 2015; Sabaté et al, 2015; Ma et al, 2016). The impact of CYP2C19 variants on risk of MACE is controversial (Mega et al, 2009, 2010b; Bauer et al, 2011; Han et al, 2015).…”

Study of the Association of <b><i>PEAR1</i></b>,<b><i> P2Y12</i></b>, and <b><i>UGT2A1</i></b> Polymorphisms with Platelet Reactivity in Response to Dual Antiplatelet Therapy in Chinese Patients

“…Dual antiplatelet therapy with clopidogrel and aspirin has become an effective therapeutic strategy in patients with ACS [2], but there is inevitably individual variability in platelet aggregation, resulting in different clinical outcomes [3-6]. The reasons for these phenotypic differences in platelet reactivity are not completely known, but genetic factors may make crucial contributions to such variability [7-9]. …”