Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects.
Background: Ticagrelor, the first reversible P2Y12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease.Objective: The objectives of this study...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 74; no. 6; pp. 745 - 755 |
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| Autores principales: | , , , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Springer Nature
Jun2018
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=129528354&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 129528354 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Jun2018 vid: 74 iid: 6 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 129528354 129528354 129528354 10.1007/s00228-018-2427-3 129528354 ppf: 745 ppct: 10 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects. aug: au: Liu, Shuaibing Xue, Ling Shi, Xiangfen Sun, Zhiyong Zhu, Zhenfeng Zhang, Xiaojian Tian, Xin affil: Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China sug: subj: Platelet Aggregation Inhibitors Pharmacodynamics Platelet Aggregation Inhibitors Pharmacokinetics Models, Theoretical Platelet Aggregation Drug Effects Platelet Aggregation Inhibitors Metabolism Human China Chinese Persons Male Platelet Aggregation Inhibitors Administration and Dosage Polymorphism, Genetic Biotransformation Enzymes Polymerase Chain Reaction Genotype Sequence Analysis Platelet Aggregation Inhibitors Blood Absorption Simulations Dose-Response Relationship, Drug Male ab: Background: Ticagrelor, the first reversible P2Y12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease.Objective: The objectives of this study were to establish a population pharmacokinetics (PK) and pharmacodynamics (PD) model of ticagrelor and to provide a theoretical basis for the optimization of ticagrelor treatment in clinic.Methods: A single oral dose of 180 mg ticagrelor was administered to 14 healthy male subjects in a randomized study. Common single-nucleotide polymorphisms (SNPs) in biotransformation enzymes CYP3A4 and CYP3A5 (CYP3A4*1G and CYP3A5*3) were genotyped by PCR-direct sequencing. Blood samples were collected to measure plasma concentrations of ticagrelor and its active metabolite AR-C124910XX and maximal platelet inhibition. Various models were evaluated to characterize the pharmacokinetics of ticagrelor and AR-C124910XX as well as their PK-PD relationship. Covariates that may potentially affect PK or PD of ticagrelor and AR-C124910XX were included and assessed. Simulation for dosage regimen was performed based on the final PK-PD model.Results: Ticagrelor and AR-C124910XX PK were best described by a two-compartment model with first-order transit absorption model. CYP3A4*1G increased clearance for AR-C124910XX, but had no significant effect on ticagrelor clearance. The relationship between concentration and platelet response of ticagrelor was best described by a turnover model. Simulation results indicated that a lower dosage regimen of 30 mg maintenance dose (MD) could produce an anticipated anti-platelet response in comparison to the routine clinical dosage regimen (180 mg loading dose (LD), 90 mg MD).Conclusion: Our study developed a population PK-PD model for ticagrelor and further simulation for dosage regimen was performed based on the final model. Compared to the current recommended dosage regimen (180 mg LD, 90 mg MD), our simulation result of a relatively lower dose (30 mg MD) could also obtain an acceptable anti-platelet response, which may provide a reference for further dosage regimen design in Chinese population. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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