Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.

نویسندگان

  • Christoph Varenhorst
  • Niclas Eriksson
  • Åsa Johansson
  • Bryan J Barratt
  • Emil Hagström
  • Axel Åkerblom
  • Ann-Christine Syvänen
  • Richard C Becker
  • Stefan K James
  • Hugo A Katus
  • Steen Husted
  • Ph Gabriel Steg
  • Agneta Siegbahn
  • Deepak Voora
  • Renli Teng
  • Robert F Storey
  • Lars Wallentin
چکیده

AIMS Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. METHODS AND RESULTS A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 × 10(-6)) and ARC (P = 4.6 × 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10(-15) and rs56324128, P = 9.7 × 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. CONCLUSION In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment. CLINICAL TRIAL REGISTRATION NCT00391872.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Effect of CYP3A4∗1G and CYP3A5∗3 Polymorphisms on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects

Ticagrelor is the first reversible, direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y12 receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. CYP3A polymorphisms have been well docu...

متن کامل

Ticagrelor enhances adenosine-mediated antiplatelet effect in acute coronary syndrome patients-a prospective cohort study

Background: Ticagrelor could exert a potential higher antiplatelet effect than clopidogrel and inhibit cellular uptake of adenosine, which was associated with several cardiovascular effects. We aimed to explore the association of plasma adenosine concentration (APC) and antiplatelet effect with clopidogrel or ticagrelor in acute coronary syndrome (ACS) patients receiving dual antiplatelet thera...

متن کامل

Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect.

OBJECTIVE In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y12-receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury...

متن کامل

Circulating Levels of Pro-inflammatory Cytokines in Patients with Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Background: Pro-inflammatory cytokines are associated with systemic inflammatory responses. Objective: To investigate the levels of pro-inflammatory cytokines (IL-1b, IL-6, and TNF-a) in patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) compared to healthy individuals. Methods: This case-control study was c...

متن کامل

Ticagrelor: The First Reversibly Binding Oral P2Y12 Receptor Antagonist

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y(12) receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate gr...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • European heart journal

دوره 36 29  شماره 

صفحات  -

تاریخ انتشار 2015