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

Abstract

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.

• Authors: 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, PLATO Investigators
• Journal: European heart journal (Eur Heart J) Vol. 36 Issue 29 Pg. 1901-12 (Aug 01 2015) ISSN: 1522-9645 [Electronic] England
• PMID: 25935875 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected].

Chemical References

• AR C124910XX
• Liver-Specific Organic Anion Transporter 1
• Organic Anion Transporters
• Purinergic P2Y Receptor Antagonists
• SLCO1B1 protein, human
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• UGT2B7 protein, human
• Glucuronosyltransferase
• Ticagrelor
• Adenosine

Topics

• Acute Coronary Syndrome (blood, drug therapy, genetics)
• Adenosine (analogs & derivatives, blood, metabolism, pharmacokinetics)
• Adult
• Cytochrome P-450 CYP3A (genetics)
• Female
• Genome-Wide Association Study
• Genotype
• Glucuronosyltransferase (genetics)
• Humans
• Liver-Specific Organic Anion Transporter 1
• Male
• Middle Aged
• Organic Anion Transporters (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Purinergic P2Y Receptor Antagonists (blood, pharmacokinetics)
• Ticagrelor
• Treatment Outcome