Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects
Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects
复制标题
替格瑞洛和 AR-C124910XX 在中国健康男性受试者中的群体药代动力学和药效学
DOI：
10.1007/s00228-018-2427-3
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发表时间：
2018-06-01
影响因子：
2.9
通讯作者：
Tian, Xin
中科院分区：
文献类型：
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作者：
Liu, Shuaibing;Xue, Ling;Tian, Xin
背景：替格瑞洛是第一个可逆的p2y12受体拮抗剂，在健康受试者和稳定冠状动脉疾病患者中，都比氯吡格雷表现出更快的起效和抗血小板作用，以及更一致的血小板抑制作用。目的建立替格瑞洛人群药代动力学（PK）和药效学（PD）模型，为替格瑞洛临床用药优化提供理论依据。方法对14例健康男性受试者随机给予替格瑞洛180 mg单次口服。采用PCR-direct测序方法对生物转化酶CYP3A4和CYP3A5常见单核苷酸多态性（CYP3A4*1G和CYP3A5*3）进行基因分型。采集血样，测定替格瑞洛及其活性代谢物AR-C124910XX的血浆浓度和最大血小板抑制作用。我们评估了各种模型，以表征替格瑞洛和AR-C124910XX的药代动力学及其PK-PD关系。纳入并评估了可能影响替格瑞洛和AR-C124910XX的PK或PD的协变量。根据最终的PK-PD模型进行给药方案模拟。结果替格瑞洛和AR-C124910XX PK均采用一阶传递吸收双室模型。CYP3A4*1G增加AR-C124910XX的清除率，但对替格瑞洛清除率无显著影响。替格瑞洛浓度与血小板反应之间的关系最好用周转模型来描述。模拟结果表明，与常规临床给药方案（180 mg负荷剂量（LD）， 90 mg MD）相比，30mg维持剂量（MD）较低的给药方案可以产生预期的抗血小板反应。结论本研究建立了替格瑞洛人群PK-PD模型，并在此基础上进一步模拟给药方案。与目前推荐的剂量方案（180mg LD, 90mg MD）相比，我们的模拟结果显示，相对较低的剂量（30mg MD）也能获得可接受的抗血小板反应，这可能为中国人群进一步的给药方案设计提供参考。
BackgroundTicagrelor, the first reversible P2Y12receptor 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.ObjectiveThe 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.MethodsA 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.ResultsTicagrelor 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).ConclusionOur 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.