Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects

Zhu, Qian; Zhong, Weijie; Wang, Xipei; Mai, Liping; He, Guangbin; Chen, Jiyan; Tang, Lan; Liu, Shuwen; Lai, Wen‐Ter; Zhong, Shilong

doi:10.3389/fphar.2019.00209

Cited by 13 publications

(17 citation statements)

References 44 publications

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“…Nevertheless, concurrent with a previous study, the observed ABCB1 variants, such as rs2235048, rs2235047, rs1045642, rs2235013, and rs2235033, were not associated with the PK of ticagrelor (Teng, 2015). In addition, the remaining CYP2C9, CYP2B6, UGT2B7, and SLCO1B1 polymorphisms had no effect on the PK of ticagrelor and its metabolite AR-C124910XX, which is consistent with previous findings (Zhou et al, 2011;Zhu et al, 2019).…”

Section: Discussionsupporting

confidence: 89%

“…CYP2C19*2 and CYP2C19p3 appeared to be the most common alleles in the Chinese population. A previous study reported that CYP2C19*3 G/G carriers had a higher T max than G/A carriers after a single dose of ticagrelor (Zhu et al, 2019). In our study, CYP2C19*2 had no effect on the PK of ticagrelor.…”

Section: Discussioncontrasting

confidence: 53%

“…Ticagrelor is a putative P-glycoprotein substrate that could be encoded by ABCB1. As an efflux transporter, P-glycoprotein significantly affects drug disposition since it is expressed in intestinal mucosal epithelial cells, hepatocytes, and capillary endothelial cells (Zhu et al, 2019;Ji et al, 2021). It is reasonable to speculate that ABCB1 polymorphisms are associated with the plasma exposure of ticagrelor.…”

Section: Discussionmentioning

confidence: 99%

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Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

et al. 2022

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Background: Ticagrelor belongs to a new class of P2Y12 receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX.Methods: The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography–tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing.Results: Female participants had a higher maximum plasma concentration/weight ratio (Cmax/W; p < 0.001) and a shorter half-life (T1/2; p < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/W; p < 0.001), and longer T1/2 (p < 0.001) and time to reach the maximum plasma concentration (Tmax; p < 0.001), as well as a lower apparent drug clearance (CL/F; p < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher Cmax/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (Vd/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher Cmax/W (p < 0.001) and AUC/W (p < 0.01), shorter Tmax (p < 0.001), and lower CL/F (p < 0.001) and Vd/F (p < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the CYP4F2 rs2074900 A/A carriers were associated with higher Cmax/W and AUC/W and lower CL/F and Vd/F than the CYP4F2 rs2074900 A/G and G/G carriers.Conclusion: This study is the first to show that the CYP4F2 rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.

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Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

et al. 2022

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“…The clinical application of genetic testing to optimize therapeutic strategies lacks sufficient evidence that understanding of the genetic determinants of ticagrelor. 16 …”

Section: Introductionmentioning

confidence: 99%

“…The clinical application of genetic testing to optimize therapeutic strategies lacks sufficient evidence that understanding of the genetic determinants of ticagrelor. 16 Therefore, a prospective experiment involving 100 Chinese patients with the percutaneous coronary intervention was designed. SNP and clinical characteristics were associated to antiplatelet response and bleeding event after ticagrelor treatment.…”

Section: Introductionmentioning

confidence: 99%

Identification of Potential Biological Factors Affecting the Treatment of Ticagrelor After Percutaneous Coronary Intervention in the Chinese Population

Yuan¹,

Shi²,

Gao³

et al. 2022

PGPM

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Background Generally, many individual factors can affect the clinical application of drugs, of which genetic factors contribute more than 20%. Ticagrelor is a new class of receptor inhibitors receptor antagonist of P2Y12 and is used as an antiplatelet agents. But it is not affected by the influence of CYP2C19 polymorphism. With lack of predicted biomarkers, especially the research data of Chinese, it has the important significance in studying individual differences of ticagrelor in the antiplatelet efficacy and safety, through pharmacogenomics research. Methods Whole-exome sequencing (WES) was performed in 100 patients after PCI with ticagrelor treatment. Clinical characteristics and WES of patients were used to performed genome-wide association analysis (GWAS), region-based tests of rare DNA variant to find the influencing factors of antiplatelet effect to ticagrelor and bleeding events. Co-expression, protein–protein interaction (PPI) network and pathway enrichment analysis were then used to find possible genetic mechanisms. Atlas of GWAS ( https://atlas.ctglab.nl/ ) were used for external data validation. Results DNAH17, PGS1 and ABCA1 as the potential variant genes are associated with the expected antiplatelet effect to ticagrelor. The affected pathways may include the synthesis and metabolism of lipoprotein cholesterol and the catabolic process of pyrimidine-containing compound (GO:0072529). Age, sex and PLT were found may be potential factors for ticagrelor bleeding events. Conclusion We systematically identified new genetic variants and some risk factors for reduced efficacy of ticagrelor and highlighted related genes that may be involved in antiplatelet effects and bleeding event of ticagrelor. Our results enhance the understanding of the absorption and metabolic mechanisms that influence antiplatelet response to ticagrelor treatment. Trial Registration ClinicalTrials.gov Identifier: NCT03161002. First Posted: May 19, 2017. https://clinicaltrials.gov/ct2/show/study/NCT03161002 .

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Sample pretreatment and HPLC determination of antiplatelet drug ticagrelor in blood plasma from patients with acute coronary syndromes

Sunarić

Mladenov²,

Nikolić

et al. 2023

Biomedical Chromatography

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A simple HPLC method was developed for the determination of antiplatelet drug ticagrelor (TCG) in blood. Sample preparation and extraction conditions were investigated and optimized. The preparation of blood plasma was investigated by protein precipitation using perchloric acid, methanol, acetonitrile (ACN), and trifluoroacetic acid. Protein precipitation using ACN was found to be the most suitable. Chromatographic separation of TCG was performed on a C18 column with a mobile phase consisting of ACN and 15 mM ammonium acetate buffered at pH 8.0. The method was applied to determine TCG in blood plasma of patients who had a heart attack. Blood samples were collected 1.5 h after the administration of the initial loading dose of the antiplatelet drug. The average concentration of TCG was found to be 0.97 ± 0.53 μg/ml. The developed method proved to be very selective, without interferences from other endogenous substances and the influences of possible coadministered drugs. The limits of detection and quantification estimated by the signal‐to‐noise ratio in real samples were 0.24 and 0.4 μg/ml, respectively. The developed method is simple and can be easily applied in clinics and emergency cardiac situations after the initial loading dose of TCG in the first few hours of a heart attack.

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Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects

Cited by 13 publications

References 44 publications

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

Identification of Potential Biological Factors Affecting the Treatment of Ticagrelor After Percutaneous Coronary Intervention in the Chinese Population

Sample pretreatment and HPLC determination of antiplatelet drug ticagrelor in blood plasma from patients with acute coronary syndromes

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