No Effect of <i>SLCO1B1</i> and <i>CYP3A4/5</i> Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

Abstract

Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers. Key words ticagrelor; pharmacokinetics; pharmacodynamics; SLCO1B1; CYP450Ticagrelor is the first reversible P2Y12 receptor inhibitor that provides faster onset/offset of pharmacological action and more consistent platelet inhibition compared to clopidogrel. It is recommended for combination therapy with aspirin in patients presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was observed to reduce the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but showed similar rates of major bleeding compared with clopidogrel. 1)As compared with clopidogrel, ticagrelor does not require metabolic activation to exert its antiplatelet effects. The major active metabolite of ticagrelor, AR-C124910XX (ARC), is formed via the hepatic CYP enzyme, CYP3A4 and CYP3A5.2) ARC is present in the blood at about 30-40% of the concentration of ticagrelor with a similar antiplatelet activity. Like other antiplatelet drugs, ticagrelor also shows interindividual variation in platelet inhibitory response in patients with ACS.3)At present, no genetic determinants for the ticagrelor pharmacodynamics (PD) are known, [4][5][6] although several genetic loci (SLCO1B1, UGT2B7, and CYP3A4) were reported to affect the pharmacokinetics (PK) of ticagrelor in Caucasian patients with ACS. 7) However, single nucleotide polymorphisms (SNPs) in the PK related genes showed no effects on efficacy or safety of ticagrelor. 7) Our previous studies r...

CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel

“…This suggests that CYP3A5 is not essential in the metabolism of ticagrelor, at least when CYP3A4 activity is normal. These results are in accordance with a recent study in which the CYP3A5*3 allele did not affect ticagrelor pharmacokinetics or pharmacodynamics in 18 healthy Chinese volunteers …”

Impact of Implementing CYP2C19 Genotype-Guided Antiplatelet Therapy on P2Y12 Inhibitor Selection and Clinical Outcomes in Acute Coronary Syndrome Patients After Percutaneous Coronary Intervention: A Real-World Study in China

“…Ticagrelor is a P2Y 12 inhibitor that acts directly on platelets, and its efficacy is hardly affected by CYP2C19 gene polymorphisms (Wallentin et al, 2010;Li et al, 2017). The PLATO trial confirmed that ticagrelor is superior to clopidogrel in reducing adverse cardiovascular events in patients with ACS (Wallentin et al, 2009).…”

The Impact of Clinical and Genetic Factors on Ticagrelor and Clopidogrel Antiplatelet Therapy

“…However, these variants had no associations with cardiovascular death, MI, stroke, noncoronary artery bypass grafting-related bleeds or dyspnea [22]. It is worth noting that SLCO1B1 rs113681054 and rs4149056, CYP3A4 rs2242480 and CYP3A5 rs776746 had no significant future science group Ticagrelor pharmacogenomics Research Article effect on pharmacokinetics and pharmacodynamics of ticagrelor [23]. Thus, currently there are no genetic polymorphisms identified which may explain the antiplatelet activity of ticagrelor.…”