Liu Zhiyan, Liu Yaou, Mu Guangyan, Zhang Hanxu, Zhou Shuang, Wang Zhe, Xie Qiufen, Wang Zining, Guo Ninghong, Huang Jie, Guo Liping, Huang Yan, Li Jian, Yang Guoping, Yuan Dongdong, Song Hongtao, Jiang Jie, Xiang Qian, Cui Yimin
Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China.
School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
Clin Pharmacokinet. 2023 Mar;62(3):435-447. doi: 10.1007/s40262-022-01208-0. Epub 2023 Feb 3.
Data available for pharmacokinetics (PK)/pharmacodynamics (PD) of ticagrelor and significant endogenous/exogenous factors or biomarkers related to bleeding events in both healthy and clinical patients are limited.
Based on PK and PD data from multicenter healthy subjects and patients, we aimed to establish an integrated approach towards population PK (pop PK) and the PD model of ticagrelor.
This study was conducted as a multicenter, prospective clinical registration study involving both healthy subjects and clinical patients. The integrated Pharmacokinetic/pharmacodynamic (PK/PD) models were characterized based on PK/PD [ticagrelor concentration, aggregation baseline (BASE), P2Y12 response unit (PRU) and inhibition rate (INHIBIT)] data from 175 healthy volunteers. The model was corrected by sparse PD (BASE, PRU and INHIBIT) data from 208 patients with acute coronary syndrome (ACS). The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored.
A one-compartment, linear model with first-order absorption was adopted as PK model. Food status (FOOD) and body weight (WT) significantly influenced clearance and improved the fitting degree of the PK model, while SEX was selected as the covariates of the PD model. For patients taking ticagrelor 90 mg, the peak value [mean (95% CI)] of PRU was 355.15 (344.24-366.06) and the trough value was 3.64 (3.14-4.15). The PRU mean parameters were basically within the expected range (80-200) of the literature suggestions.
A fixed dose of ticagrelor, without adjusting the dosing regimen other than covariates of FOOD/WT/SEX, could be used in patients with acute coronary syndromes, and the standard regimen could be used in Chinese patients from the perspective of exposure.
关于替格瑞洛的药代动力学（PK）/药效学（PD）以及健康受试者和临床患者中与出血事件相关的重要内源性/外源性因素或生物标志物的可用数据有限。
基于多中心健康受试者和患者的PK和PD数据，我们旨在建立一种针对替格瑞洛群体药代动力学（群体PK）和PD模型的综合方法。
本研究作为一项多中心、前瞻性临床注册研究进行，纳入了健康受试者和临床患者。基于175名健康志愿者的PK/PD [替格瑞洛浓度、聚集基线（BASE）、P2Y12反应单位（PRU）和抑制率（INHIBIT）]数据对综合药代动力学/药效学（PK/PD）模型进行了表征。该模型通过208例急性冠状动脉综合征（ACS）患者的稀疏PD（BASE、PRU和INHIBIT）数据进行校正。探讨了1年内PD生物标志物与临床相关出血之间的相关性。
PK模型采用具有一级吸收的单室线性模型。食物状态（FOOD）和体重（WT）显著影响清除率并提高了PK模型的拟合度，而性别（SEX）被选为PD模型的协变量。对于服用90 mg替格瑞洛的患者，PRU的峰值[均值（95%CI）]为355.15（344.24 - 366.06），谷值为3.64（3.14 - 4.15）。PRU平均参数基本在文献建议的预期范围（80 - 20）内。
对于急性冠状动脉综合征患者，可不调整给药方案（除FOOD/WT/SEX协变量外）使用固定剂量的替格瑞洛，从暴露角度来看，中国患者可使用标准方案。
