The effects of CES1A2 A(−816)C and CYP2C19 loss-of-function polymorphisms on clopidogrel response variability among Chinese patients with coronary heart disease

Xie, Cheng; Ding, Xiaoliang; Gao, Jie; Wang, Haipeng; Hang, Yongfu; Zhang, Hua; Zhang, Jingjing; Jiang, Bin; Miao, Liyan

doi:10.1097/fpc.0000000000000035

Cited by 39 publications

(29 citation statements)

References 28 publications

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“…Several recent studies report an impact of CES1 polymorphisms on clopidogrel response in patients (Lewis et al, 2013b; Tarkiainen et al, 2015; Xie et al, 2014; Zou et al, 2014). This is consistent with findings of the PAPI study, which show that clop-AM plasma concentrations are significantly higher in CES1 G143E-allele carriers vs. wild-type subjects (30.3 ± 6.1 vs. 19.0 ± 0.4 ng/ml, P = 0.001).…”

Section: Discussionmentioning

confidence: 99%

Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults

Jiang

Samant

Lewis

et al. 2016

European Journal of Pharmaceutical Sciences

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Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel’s dose–concentration–response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel’s bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.

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Section: Discussionmentioning

confidence: 99%

Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults

Jiang

Samant

Lewis

et al. 2016

European Journal of Pharmaceutical Sciences

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“…Despite control for various polymorphisms besides those in ABCB1, and for lifestyle factors and co-medications, the variability has remained largely unexplained. With regard to outcome, several clopidogrel trials have been published, but the results were inconsistent and mostly not significant [164][165][166]. Nonetheless, Simon et al [157] reported an association between the 3435TT genotype and an increased risk of cardiovascular events.…”

Section: Clopidogrelmentioning

confidence: 97%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

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“…In patients with acute coronary disease under clopidogrel treatment, the on-treatment platelet reactivity in the individuals carrying the CES1 143E-allele was also significantly lower than that in 143G-homozygotes [68]. On the other hand, the CES1A -816A/C allele, which has been reported to cause significantly enhanced transcriptional activity of CES gene [69], has been found to be associated with either significantly increased or reduced on treatment platelet reactivity in patients with coronary heart disease [70, 71]. These findings suggests that more research needs to be done to conclusively characterize the impact of genetic polymorphism in CES1 on clopidogrel response.…”

Section: Covariates That Affect Clopidogrel Dose/pk/pdmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

et al. 2015

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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.

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The effects of CES1A2 A(−816)C and CYP2C19 loss-of-function polymorphisms on clopidogrel response variability among Chinese patients with coronary heart disease

Abstract: The CES1A2 -816C and the CYP2C19 LOF alleles were associated with attenuated platelet reactivity to clopidogrel. CYP2C19 LOF was also predictive of ST; however, the association between the CES1A2 -816C allele and development of ST requires further study.

Cited by 39 publications

References 28 publications

Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults

Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

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