Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor

Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y(12) receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel. Numerous studies and wide use in clinical practice have established the value of this approach in the treatment of ACS. However, clopidogrel treatment has a number of limitations, including a delayed onset of action due to the need for metabolic activation, variable and reduced antiplatelet effects in patients with certain genotypes, and prolonged recovery of platelet function due to irreversible P2Y(12) receptor binding. Prasugrel, a new thienopyridine, has demonstrated more consistent inhibition of platelet aggregation (IPA) than clopidogrel, although this thienopyridine also requires metabolic activation and treatment is associated with a significantly increased risk of life-threatening and fatal bleeding. The recently approved oral antiplatelet agent ticagrelor has the potential to overcome some of the limitations of current therapy due to its unique pharmacokinetic and pharmacodynamic profiles. It is a member of a new chemical class, the cyclopentyltriazolopyrimidines, and is a potent P2Y(12) receptor antagonist. Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.3-2.0 hours. Ticagrelor does not require metabolic activation to an active form and binds rapidly and reversibly to the P2Y(12) receptor. As well as exerting effects via platelet P2Y(12) receptors, ticagrelor may confer additional benefits via inhibition of non-platelet P2Y(12) receptors. The pharmacokinetic profile of ticagrelor is not significantly affected by age, gender or administration with food, nor by prior treatment with, or responsiveness to, clopidogrel. Ticagrelor is primarily metabolized via the cytochrome P450 (CYP) 3A4 enzyme, rapidly produces plasma concentration-dependent IPA that is greater and more consistent than that observed with clopidogrel, and can also enhance platelet inhibition and overcome non-responsiveness in patients previously treated with clopidogrel. Importantly, the pharmacodynamic characteristics of ticagrelor are not influenced by CYP2C19 and ABCB1 genotypes. This article summarizes our current knowledge regarding the pharmacokinetic, pharmacodynamic and pharmacogenetic profile of ticagrelor.     

Ticagrelor: a review of its use in the management of acute coronary syndromes

Ticagrelor (Brilique?; Brilinta?), a cyclopentyl-triazolo-pyrimidine antiplatelet agent, is the first oral antagonist of the P2Y(12) receptor to offer reversible receptor binding. It is indicated in the EU for the prevention of atherothrombotic events in adults with acute coronary syndromes (ACS) [unstable angina pectoris, ST-segment elevation myocardial infarction [STEMI] or non-STEMI), including those managed medically or with percutaneous coronary intervention or coronary artery bypass grafting (CABG). Ticagrelor provides selective and reversible inhibition of adenosine diphosphate-induced platelet aggregation, with a faster onset and offset of action than that of clopidogrel, and is effective in the treatment of patients with ACS, with or without ST-segment elevation. In the large, randomized, double-blind, multicentre PLATO trial conducted in this patient population, ticagrelor was more effective than clopidogrel in terms of preventing ischaemic events over 12 months, providing a significantly lower risk of the primary composite endpoint of myocardial infarction, stroke or death from vascular causes, and was associated with an overall mortality benefit. The risk of major bleeding with ticagrelor, including bleeds related to CABG, did not differ from that seen with clopidogrel in this study, although ticagrelor was associated with more non-CABG-related major bleeds and fatal intracranial bleeding, albeit the latter bleeding events were rare. Further long-term and comparative efficacy and tolerability data are required to definitively position ticagrelor with respect to other antiplatelet agents, including prasugrel. However, the clinical data currently available indicate that ticagrelor is a promising option for the treatment of patients with ACS and may be of particular use in those at high risk of ischaemic events or unresponsive to clopidogrel.     

Efficacy and safety of ticagrelor in patients with acute coronary syndrome: A meta‐analysis of randomized controlled trials

Acute coronary syndrome (ACS) is a dangerous and urgent clinical pattern of coronary artery disease. Aspirin and adenosine diphosphate P2Y₁₂ receptor antagonists are the standard dual anti‐platelet therapy for patients with ACS. Ticagrelor is a new oral antagonist of the adenosine diphosphate P2Y₁₂ receptor. Randomized controlled trials (RCTs) have evaluated the efficacy and safety of ticagrelor compared to clopidogrel or prasugrel in patients with ACS, obtaining conflicting results. Thus, we conducted a meta‐analysis of these RCTs to determine the efficacy and safety of ticagrelor in patients with ACS. Results of the meta‐analysis indicate that ticagrelor decreased the risk of major adverse cardiovascular events (MACE) and all‐cause death, but increased the risk of bleeding events. In Asiatic patients, analysis indicates that ticagrelor did not decrease the risk of MACE and all‐cause death, while increasing the risk of bleeding events. Together, this meta‐analysis suggests that ticagrelor was more effective, but less safe than clopidogrel and prasugrel in patients with ACS. Subgroup analysis indicates that ticagrelor was not more effective, although less safe than clopidogrel in Asiatic patients, thus more evidence is needed to further evaluate the efficacy and safety of ticagrelor in Asiatic patients.     

Pharmacokinetics and pharmacodynamics of ticagrelor in the treatment of cardiac ischemia

Introduction: After acute coronary syndromes (ACS), the so-called dual antiplatelet therapy (DAPT), which usually consists of low-dose of aspirin in combination with a thienopyridine (clopidogrel, prasugrel) or with a cyclopentyltriazolopyrimidine (ticagrelor), reduces the risk of ischemic events. Ticagrelor, un particular, is an effective drug as it isn’ a prodrug, doesn’t require metabolic activation and demonstrates a rapid onset and faster offset of action.

Areas covered: This article evaluates the pharmacokinetics, efficacy, safety and tolerability of ticagrelor during DAPT after ACS and its potential use beyond the canonical twelve months after PCI. The review discusses studies comparing: ticagrelor and clopidogrel (DISPERSE, DISPERSE-2, PLATO, RESPOND Trial, ONSET/OFFSET Trials), ticagrelor and placebo (PEGASUS TIMI 54 Trial).

Expert opinion: For ACS patients, the PLATO trial showed that ticagrelor was superior to clopidogrel in the reduction of cardiovascular death, myocardial infarction and stroke. PEGASUS TIMI 54 showed that patients in whom ischemic events and cardiovascular death outweigh the risk of life-threatening bleeding, may benefit from prolonged ticagrelor-based dual antiplatelet therapy, over 12 months. This strategy has been recently approved by the ACC/AHA guidelines. Further studies are needed to evaluate and eventually validate the role of the prolonged DAPT in patients treated with new generation stents.     

抗血小板新药替卡格雷取代氯吡格雷的探讨

近年来,美国食品药品监督管理局（FDA）已经批准口服抗血小板药物替卡格雷配合使用低剂量阿司匹林,以降低急性冠脉综合征（ACS）血栓性心血管事件的发生率,替卡格雷将是氯吡格雷有力的竞争对手。虽然替卡格雷比氯吡格雷药效更好,但其存在用药依从性问题。另外,替卡格雷联合阿司匹林使用的剂量具有一个黑框警告,并且替卡格雷成本比氯吡格雷高得多。本文就两者的药物特征及临床治疗特点做进一步的阐述,分析成因。     

Ticagrelor for the treatment of arterial thrombosis

Importance of the field: High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y₁₂ blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y₁₂ receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y₁₂ receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor.

Areas covered in this review: We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y₁₂ receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about ‘AZD6140’ and ‘ticagrelor’ in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings.

What the reader will gain: This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y₁₂ receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers.

Take home message: Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use.     

新型抗血小板药替卡格雷

替卡格雷为第一个可逆结合的、直接起效的、口服给药的血小板二磷酸腺苷P2Y12受体拮抗剂,比氯吡格雷起效更快,对血小板凝集的抑制作用更强。2011年7月20日,美国FDA批准替卡格雷用于降低急性冠脉综合征(acute coronary syndrome,ACS)患者的血栓性心血管事件的发生率。与氯吡格雷相比,替卡格雷起效更快,对血小板聚集的抑制作用更强,能显著降低心血管死亡、心肌梗死或卒中的发生率。在有效治疗的同时,替卡格雷并未显著增加主要出血事件的发生率。联合用药时,阿司匹林的维持剂量应为75～100 mg.d-1。本文对替卡格雷药理学特性、临床价值及不良反应进行综述。     

Ticagrelor. Acute coronary syndromes: nothing new

Several revascularisation methods are effective in patients with acute coronary syndromes. Standard antithrombotic treatment combines heparin and aspirin during the acute phase, followed by long-term aspirin therapy. The only proven advantage of adding clopidogrel is for patients who undergo angioplasty with stenting. Ticagrelor is an antiplatelet drug belonging to a different chemical class than clopidogrel. Its chemical structure resembles that of adenosine. Ticagrelor has been authorised in the European Union for patients with acute coronary syndromes, in combination with aspirin. Clinical evaluation is mainly based on a double-blind randomised trial comparing ticagrelor + aspirin versus clopidogrel + aspirin in 18 624 patients who underwent angioplasty (64% of patients), coronary artery bypass grafting (10%), or who received medical treatment only. Half of the patients were treated for at least 9 months. After 12 months of treatment, compared to the clopidogrel group, overall mortality appeared to be significantly lower in the ticagrelor group (4.5% versus 5.9%), along with cardiovascular mortality (4.0% versus 5.1%). Symptomatic myocardial infarction was also less frequent (5.8% versus 6.9%), but not stroke (about 1.4% in both groups). Ticagrelor did not statistically significantly reduce overall mortality in patients who had angioplasty with stenting, but stent thrombosis was less frequent than with clopidogrel (2.9% versus 3.8%). In combination with aspirin, ticagrelor provoked more bleeding than clopidogrel, based on the definition used in the trial (16.1% versus 14.6%). In contrast, the rate of major bleeding was similar in the two groups (11.5%), including fatal bleeding (0.3%). The adverse effect profile of ticagrelor resembles that of adenosine in certain respects. For example, dyspnoea was more frequent with ticagrelor than with clopidogrel (13.8% versus 7.8%), as were conduction disorders and ventricular pauses at the beginning of treatment (5.8% versus 3.6%). There were also more cases of hyperuricaemia and elevated creatinine levels with ticagrelor. Ticagrelor and its active metabolite are substrates and inhibitors of cytochrome P450 isoenzymes and P-glycoprotein, creating a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely to occur, especially with antithrombotic agents and heart-rate-lowering drugs. In practice, in patients with an acute coronary syndrome treated with angioplasty and stenting, and who are also receiving aspirin, it remains to be shown whether the harm-benefit balance of ticagrelor is clearly better than that of clopidogrel. In other settings, there is no firm evidence that ticagrelor is better than aspirin alone.     

Treating acute coronary syndromes with new antiplatelet drugs: the mortality issue with prasugrel and ticagrelor

Abstract

Acute coronary syndromes (ACS) are the leading cause of mortality in Western countries. Until a few years ago, the antiplatelet drug to be administered in association with aspirin was indisputably clopidogrel. Recent data from randomized trials conducted in ACS patients have shown that the new oral antiplatelet regimens, prasugrel and ticagrelor, are associated with a significant reduction in cardiovascular events, as compared to clopidogrel. Moreover ticagrelor reduced both all-cause and cardiovascular mortality as compared to clopidogrel in the PLATO trial. However, there are intrinsic differences between the trials design and among the enrolled ACS populations, that make complex the generalization of the mortality results in the whole spectrum of ACS patients. We aimed to provide further insights into the unresolved mortality issues raised in the PLATO and TRITON–TIMI 38 trials, by analysing the effects of ticagrelor and prasugrel in the ACS populations included in the respective trials.     

Review of pharmacoeconomic evaluation of genotype-guided antiplatelet therapy

Introduction: Clopidogrel is an antiplatelet agent widely prescribed for acute coronary syndrome (ACS), and it is activated by the CYP enzyme system to active metabolite. CYP2C19 loss-of-function (LOF) allele(s) affect the responsiveness of clopidogrel, but not the new antiplatelet agents (prasugrel and ticagrelor). We reviewed the pharmacoeconomic studies on genotype-guided use of new antiplatelet agents.

Areas covered: A literature search was conducted between the period of 2000 and 2014. Seven studies including cost-effectiveness and risk-benefit analyses of CYP2C19 genotype-guided antiplatelet therapy in ACS patients were reviewed. Genotype-guided prasugrel was found to be cost-effective when compared with universal antiplatelet therapy in four studies. Three studies showed genotype-guided ticagrelor to be cost-effective in ACS patients with percutaneous coronary intervention (PCI), and universal ticagrelor to be cost-effective in ACS patients. Drug cost of antiplatelet agents and relative risk of the new antiplatelet versus clopidogrel for clinical events were common influential factors of cost-effectiveness analyses.

Expert opinion: All studies in the present review focused on selecting antiplatelet agents for carriers of CYP2C19 LOF allele(s). Cost-effectiveness of genotype-guided use of antiplatelets was demonstrated in high-risk ACS patients.     

Ticagrelor for acute coronary syndrome?

Current guidelines from the National Institute for Clinical Excellence (NICE) recommend antiplatelet therapy comprising aspirin plus either clopidogrel or prasugrel for patients with acute coronary syndrome (ACS). However, such dual therapy increases the likelihood of bleeding compared to that with aspirin alone. Ticagrelor (Brilique - Astra-Zeneca) is a new oral antiplatelet drug recently licensed in the UK (since publication of the NICE guidelines) for use with aspirin in patients with ACS, including those managed medically or undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Here we review the place of ticagrelor in the management of people with ACS, and whether it offers advantages over standard therapy in terms of greater efficacy or lower likelihood of bleeding complications.     

Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment

Ticagrelor, a P2Y?? receptor antagonist that inhibits ADP-induced platelet aggregation (IPA), has demonstrated improved outcomes in patients with acute coronary syndromes compared with clopidogrel. Because ticagrelor undergoes extensive hepatic elimination, this study evaluated the effect of mild hepatic impairment on its pharmacokinetics, pharmacodynamics, and safety. A single oral 90-mg ticagrelor dose was administered to volunteers with and without hepatic impairment (10 with Child-Pugh class A; 10 with normal liver function). Absorption of ticagrelor and formation of its active metabolite, AR-C124910XX, were rapid in both groups. Ticagrelor exposure was higher in hepatically impaired volunteers (maximum concentration [C(max)] 12%; area under the plasma concentration-time curve from time 0 to infinity [AUC] 23%) compared with controls. AR-C124910XX exposure was also higher in hepatic impairment (C(max) 17%; AUC 66%). Ticagrelor is highly protein bound (>99.8%); the unbound fraction in plasma was comparable in volunteers with hepatic impairment and controls. Overall, IPA parameters were not significantly different between groups, and similar IPA-concentration profiles were observed. Ticagrelor was well tolerated in both groups, and no adverse events were reported. In conclusion, mild hepatic impairment resulted in modestly higher exposure to ticagrelor and AR-C124910XX, without subsequent effects on pharmacodynamics or tolerability. Based on these data, no ticagrelor dosage adjustment is needed in patients with mild hepatic impairment.     

Ticagrelor: Positive,negative and misunderstood properties as a new antiplatelet agent

相似文献   

替格瑞洛对急性冠脉综合征经皮冠状动脉介入治疗围术期血小板聚集率的影响

目的 探讨替格瑞洛对急性冠脉综合征(ACS)经皮冠状动脉介入治疗(PCI)围术期血小板聚集率(MPAR)的影响.方法 80例确诊为ACS行PCI术患者为研究对象,术前采用随机数字表法分为替格瑞洛治疗组(观察组)和氯吡格雷治疗组(对照组),每组40例.所有研究对象入院前已连续服用氯吡格雷(泰嘉) 75 mg·d-1持续7 d以上者维持原剂量,未曾服用过氯吡格雷者予以300 mg负荷剂量后75 mg·d-1维持.观察组入院前已连续服用替格瑞洛每次90 mg,2次/天,持续7 d以上者维持原剂量,未曾服用过替格瑞洛者予以180 mg负荷剂量后改标准剂量替格瑞洛(每次90 mg,2次/天)治疗.分别于治疗前、术后5 d抽取空腹外周血标本进行MPAR的测定.结果 治疗前观察组和对照组患者MPAR比较,差异无统计学意义 (P>0.05);术后5 d外周血MPAR均明显低于治疗前(P<0.05);观察组MPAR明显低于对照组(P<0.05).结论 替格瑞洛较氯吡格雷能更好地抑制ACS血管病变患者PCI围术期MPAR,降低早中期不良心血管事件的发生率,对重度冠状动脉血管病变的患者具有更好抗血小板聚集的治疗效果.     

Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y₁₂ receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day⁻¹, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median t_max 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean C_max and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with C_max and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day⁻¹ was well tolerated.     

Treating acute coronary syndromes with new antiplatelet drugs: the mortality issue with prasugrel and ticagrelor

Acute coronary syndromes (ACS) are the leading cause of mortality in Western countries. Until a few years ago, the antiplatelet drug to be administered in association with aspirin was indisputably clopidogrel. Recent data from randomized trials conducted in ACS patients have shown that the new oral antiplatelet regimens, prasugrel and ticagrelor, are associated with a significant reduction in cardiovascular events, as compared to clopidogrel. Moreover ticagrelor reduced both all-cause and cardiovascular mortality as compared to clopidogrel in the PLATO trial. However, there are intrinsic differences between the trials design and among the enrolled ACS populations, that make complex the generalization of the mortality results in the whole spectrum of ACS patients. We aimed to provide further insights into the unresolved mortality issues raised in the PLATO and TRITON-TIMI 38 trials, by analysing the effects of ticagrelor and prasugrel in the ACS populations included in the respective trials.     

Effect of clopidogrel besylate on platelet reactivity in patients with acute coronary syndromes. Comparison with clopidogrel hydrogen sulfate

Objective: The efficacy of clopidogrel therapy in patients with an acute coronary syndrome (ACS) has been established using the clopidogrel hydrogen sulfate (CHS) formulation. In this study we compared the antiplatelet effectiveness of a generic clopidogrel salt, clopidogrel besylate (CB), with the original CHS in patients with an ACS.

Research design and methods: Ninety-six ACS patients were randomized to receive a 600-mg loading dose of either CHS (n = 45) or CB (n = 51), followed by 75 mg/day. Sixty-eight patients underwent a percutaneous coronary intervention (PCI), whereas 28 were treated conservatively. Platelet aggregatory response, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, P-selectin expression and platelet–leucocyte conjugates were determined before clopidogrel loading (baseline), as well as at 5 days and at 1 month afterwards.

Results: No difference in the clopidogrel response variability was observed between patients receiving CHS or CB either at 5 days or at 1 month of follow-up. Similarly, no difference in the inhibition of platelet aggregation, P-selectin expression or in the platelet–leucocyte conjugates was observed between CHS and CB group during the follow-up.

Conclusions: There is no overall significant difference in the antiplatelet efficacy between CB and CHS during their administration in ACS patients for up to 1 month after the episode.     

替格瑞洛治疗行PCI的ST段抬高型心肌梗死合并糖尿病患者效果观察

目的:观察行PCI治疗的ST段抬高型心肌梗死(STEMI)合并2型糖尿病(DM)患者应用替格瑞洛的有效性与安全性。方法:STEMI合并2型糖尿病患者154例,随机分为替格瑞洛组79例,氯吡格雷组75例,比较分析2组治疗1,6,12个月时全因死亡率、不良心血管事件(MACE)发生率、支架内血栓发生率、左室射血分数、出血事件及呼吸困难等指标。采用血栓弹力图检测2组患者治疗5 d时血小板抑制率和抵抗率。结果:替格瑞洛组1,6,12个月时全因病死率、MACE发生率、支架内血栓发生率较氯吡格雷组比较差异无统计学意义(P>0.05);替格瑞洛组支架内再狭窄发生率低于氯吡格雷组,左室射血分数优于氯吡格雷组(P<0.05);替格瑞洛组呼吸困难发生率高于氯吡格雷组(P<0.05),但症状轻微,无需特殊治疗;2组出血事件发生率比较差异无统计学意义(P>0.05);治疗5 d时替格瑞洛组血小板抑制率高于氯吡格雷组(69.22±12.34)% vs (46.87±22.1)%(P<0.05),血小板抵抗率低于氯吡格雷组(2.53% vs 22.67%)(P<0.05)。结论:在行PCI治疗的STEMI合并DM患者中应用替格瑞洛可改善预后,且安全性好。     

Association of PEAR1 rs12041331 polymorphism and pharmacodynamics of ticagrelor in healthy Chinese volunteers

1.?Genetic polymorphisms in platelet endothelial aggregation receptor 1 (PEAR1) were associated with responsiveness to aspirin and P2Y12 receptor antagonists. This study aimed to investigate whether PEAR1 polymorphism is associated with ticagrelor pharmacodynamics in healthy Chinese subjects.

2.?The in vitro inhibition of platelet aggregation (IPA) was evaluated before and after ticagrelor incubated with platelet-rich plasma from 196 healthy Chinese male subjects. Eight polymorphisms at PEAR1 locus were genotyped. Eighteen volunteers (six in each rs12041331 genotype group) were randomly selected. After a single oral 180?mg dose of ticagrelor, plasma levels of ticagrelor and the active metabolite AR-C124910XX were measured and pharmacodynamics parameters including IPA and VASP-platelet reactivity index (PRI) were assessed.

3.?No significant difference in ticagrelor pharmacokinetics among rs12041331 genotype was observed. As compared with rs12041331?G allele carriers, AA homozygotes exhibited increased IPA after 15?μM ticagrelor incubation (p?p?p?4.?PEAR1 polymorphism may influence ticagrelor pharmacodynamics in healthy Chinese subjects.     

Genetics of platelet inhibitor treatment

Dual antiplatelet therapy with aspirin and a P2Y₁₂ receptor antagonist is the standard of care in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) because this regimen has markedly decreased the rate of cardiovascular events. The substantial variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. Baseline demographic and clinical variables contributing to the observed variability have been identified. Besides this, research within the past decade has focused on the impact of genetic polymorphisms encoding transport systems or enzymes involved in the absorption and metabolism of these drugs. Loss-of-function polymorphisms in CYP2C19 are the strongest individual variables affecting pharmacokinetics and antiplatelet response to clopidogrel, but explain no more than 5 to 12% of the variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. No genetic variables contributing to clinical outcomes of patients treated with the newer P2Y₁₂ receptor antagonists, prasugrel or ticagrelor, have been identified so far. This review aims to provide an update on the current status of genotype-based personalized therapy with clopidogrel.