Department of Cardiology, Peking University Third Hospital, Beijing, 100191, China.
Drug Clinical Trial Center, Peking University Third Hospital, Beijing, 100191, China.
Clin Pharmacokinet. 2024 Mar;63(3):303-316. doi: 10.1007/s40262-023-01335-2. Epub 2024 Jan 20.
Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups.
The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates.
Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females.
Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females.
近期研究表明，P2Y12 抑制剂的血浆浓度与临床事件（尤其是出血）之间存在相关性，这极大地影响了其临床治疗效果。因此，深入研究可能影响其血浆浓度的因素至关重要。本研究旨在总结常用 P2Y12 抑制剂（氯吡格雷、普拉格雷和替格瑞洛）的群体药代动力学/药效学（PopPKPD）模型，并评估特定个体群体的出血风险。
根据预定的纳入和排除标准，收集并总结了 P2Y12 抑制剂的 PopPKPD 模型。通过模拟对收集到的模型进行复制，用于评估影响 P2Y12 抑制剂血浆浓度的因素。根据报告的暴露-效应关系（PK/PD 相关出血和血栓性临床结局），将特殊人群的模拟结果与治疗窗进行比较，以预测不同剂量方案和累积协变量下特殊人群的出血风险。
最终纳入 12 项 PK 模拟研究，其中 7 项还包括 PD 数据，进一步进行分析，这些研究大多基于 I 期或 II 期试验。模拟结果表明，女性、体重、年龄等几个协变量对暴露量有显著影响，特殊人群的暴露量可高达普通人群的 179%。然而，经过剂量调整后，特殊人群的血药浓度可达到普通人群暴露量的±20%左右。因此，建议将替格瑞洛的维持剂量从 90mg bid 降低至 60mg bid，以降低出血风险，同时不会显著增加缺血风险，尤其是在老年、小体重的亚洲女性中。
将替格瑞洛的维持剂量从 90mg bid 降低至 60mg bid 可有效降低老年、小体重的亚洲女性出血风险，同时不会增加血栓性梗死风险。
