Pharmacokinetics and Pharmacodynamics of Ticagrelor and Prasugrel in Healthy Male Korean Volunteers

Jeon, Hae-Sun; Kim, Mi-Jo; Choi, Hyosun; Kim, Yo-Han; Kim, Eun Hwa; Kim, A-Reum; Park, Hyun-Jung; Bae, Kyun‐Seop; Lim, Hyeong‐Seok

doi:10.1016/j.clinthera.2015.01.010

Cited by 17 publications

(15 citation statements)

References 27 publications

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“…These findings are consistent with those single and multiple-ascending dose studies in healthy subjects. [13][14][15][16] SLCO1B1 encodes the organic anion transporter polypeptide (OATP1B1) expressed on the sinusoidal membrane of human hepatocytes. It mediates the hepatic uptake of many endogenous substances and xenobiotics, including many drugs.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

Biological & Pharmaceutical Bulletin

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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...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Similarly, the active metabolite of ticagrelor can also be oxidized soon after being collected. However, ticagrelor is not a prodrug and does not require metabolic activation for antiplatelet activity . The plasma parent ticagrelor can directly inhibit the aggregation of the mixed healthy platelets.…”

Section: Discussionmentioning

confidence: 99%

“…However, ticagrelor is not a prodrug and does not require metabolic activation for antiplatelet activity. 20 The plasma parent ticagrelor can directly inhibit the aggregation of the mixed healthy platelets. Thus, we suggest it was the residual drug in ticagrelor-treated plasma that inhibited the aggregation of the control platelets in Cohort 2; similarly, it would be the residual ticagrelor in the treated plasma that inhibited the donor platelets and contributed to the slow recovery manner of the reversal ticagrelor curve in Cohort 1.…”

Section: Discussionmentioning

confidence: 99%

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

Zhang

Mei

et al. 2019

Transfusion

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BACKGROUND Reversal of antiplatelet therapy is desirable in patients presenting with life‐threatening bleeding or requiring urgent surgery. This study aimed to examine ticagrelor reversal using donor platelets and to explore the effects of residual ticagrelor on donor platelets. STUDY DESIGN AND METHODS In Cohort 1, 16 healthy subjects were treated with ticagrelor 90 mg twice daily alone or in combination with aspirin 100 mg once daily for 7 days followed by single blood sampling for preparation of platelet‐rich plasma. An additional 16 healthy subjects served as controls. In Cohort 2, 16 healthy subjects were treated with ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 7 days followed by serial blood samplings for preparation of platelet‐poor plasma (PPP). An additional 16 healthy subjects served as controls. RESULTS In Cohort 1, inhibition of adenosine diphosphate–induced platelet aggregation (PLADP) by ticagrelor could not be fully reversed by mixing with up to 90% control platelets, whereas inhibition of arachidonic acid–induced platelet aggregation by aspirin was fully reversed with the addition of 60% control platelets. In Cohort 2, 10% PPP obtained from ticagrelor‐treated subjects reduced PLADP from 74% to 40% at 2 hours, 72% to 58% at 6 hours, and 73% to 59% at 10 hours, while 10% or 20% PPP obtained from clopidogrel‐treated subjects did not inhibit PLADP. CONCLUSION The antiplatelet effect of ticagrelor cannot be fully reversed by donor platelets, which could be explained by the presence of active drug. The effect of residual drug on donor platelets appears to be evident for at least 10 hours after ticagrelor ingestion.

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“…TCG, AR‐C124910XX and the active and inactive main metabolites of Prasugrel were measured in plasma using an LC–MS/MS method. Comparison of the data indicate that, although prasugrel is absorbed more rapidly, the onset of pharmacologic effect of TCG is faster, and the extent and duration of platelet inhibition are stronger and more prolonged with prasugrel (Jeon et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…A modified method was developed to quantify TCG and AR-C124910XX in other animal species. The method was successfully applied to determine plasma concentrations following administration of TCG in human volunteers and patients, and in animal safety evaluation studies (Sillen, Cook, & Davis, 2010 prasugrel is absorbed more rapidly, the onset of pharmacologic effect of TCG is faster, and the extent and duration of platelet inhibition are stronger and more prolonged with prasugrel (Jeon et al, 2015).…”

Section: Liquid Chromatography-mass Spectrometrymentioning

confidence: 99%

Analytical methodologies for the determination of ticagrelor

Kelemen

Hancu

Papp

2019

Biomedical Chromatography

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Ticagrelor is an orally administered platelet aggregation inhibitor with a cyclopentyl‐triazolopyrimidine structure; it is a selective reversible P2Y12 receptor antagonist, which prevents P2Y12‐mediated and ADP‐mediated platelet activation and aggregation. It is used to reduce the rate of cardiovascular death, myocardial infarction and stroke in patients with acute coronary syndrome or history of myocardial infarction. Several analytical methods have been published for the determination of ticagrelor in pharmaceuticals and biological materials by spectrophotometry, high‐performance liquid chromatography with ultraviolet detection and liquid chromatography coupled with tandem mass spectrometry. The purpose of the current review is to provide a systematic survey of the analytical techniques used for the determination of ticagrelor since its introduction in therapy until today.

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Pharmacokinetics and Pharmacodynamics of Ticagrelor and Prasugrel in Healthy Male Korean Volunteers

Cited by 17 publications

References 27 publications

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

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

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

Analytical methodologies for the determination of ticagrelor

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