Population pharmacokinetic analysis for dabigatran etexilate in Chinese patients with non-valvular atrial fibrillation.
Population pharmacokinetic analysis for dabigatran etexilate in Chinese patients with non-valvular atrial fibrillation.
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达比加群酯在中国非瓣膜性房颤患者中的群体药代动力学分析
DOI：
10.3389/fcvm.2022.998751
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发表时间：
2022
影响因子：
3.6
通讯作者：
Cui, Yi-min
中科院分区：
文献类型：
--
作者：
Liu, Ya-ou;Xie, Qiu-fen;Liu, Zhi-yan;Wang, Zhe;Mu, Guang-yan;Zhang, Ya-tong;Zhao, Zi-nan;Yuan, Dong-dong;Guo, Li-ping;Wang, Na;Xiang, Jing;Song, Hong-tao;Jiang, Jie;Xiang, Qian;Cui, Yi-min
我们的目的是开发一个药代动力学（PK）和药效学（PD）模型，从健康的中国受试者和现实世界的非瓣膜性房颤（NVAF）患者。我们还研究了出血事件的有意义的内在和外在因素以及相关生物标志物。在验证模型外推性能后，我们基于118例健康志愿者的丰富PK/PD数据[达比加群浓度、活化部分凝血活酶时间（APTT）、凝血酶原时间（PT）和抗因子IIa（抗FIIa）活性]和167例NVAF患者的稀疏PD数据[APTT、PT和抗FIIa]，对综合PK/PD模型进行了表征。我们还记录了一年内PD生物标志物与临床相关出血事件之间的相关性。接下来，我们使用最终的综合PK/PD模型（一级吸收的二室线性模型）评价剂量和个体协变量对PD参数的影响。年龄、高密度脂蛋白胆固醇（HDL-C）和肌酐清除率（CrCL）改善了PK模型拟合。线性直接效应PD模型描述了APTT、PT和抗FIIa抗体与血浆浓度之间的相关性。CrCL改善了PD模型拟合。在PD模型中，与APTT和PT相比，抗FIIa抗体对达比加群暴露量增加更敏感。因此，NVAF患者可使用固定剂量的达比加群，无需调整年龄和HDL-C。我们观察到出血倾向升高，APTT、PT和抗FIIa的峰值和谷值较高。应开展随机研究，以评价低剂量达比加群在中国NVAF患者中的疗效和安全性。
We aimed to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model from healthy Chinese subjects and real-world non-valvular atrial fibrillation (NVAF) patients. We also investigated meaningful intrinsic and extrinsic factors and related biomarkers for bleeding events. We characterized the integrated PK/PD models based on rich PK/PD data [dabigatran concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), and anti-factor IIa (anti-FIIa) activity] from 118 healthy volunteers and sparse PD data [APTT, PT, and anti-FIIa] from 167 patients with NVAF after verifying the model extrapolation performance. We also documented the correlations between PD biomarkers and clinically relevant bleeding events over one year. Next, we used the final integrated PK/PD model (a two-compartment, linear model with first-order absorption) to evaluate the influence of dosage and individual covariates on PD parameters. The age, high-density liptein cholesterol (HDL-C), and creatinine clearance (CrCL) improved the PK model fit. The linear direct-effects PD model described the correlation between APTT, PT, and anti-FIIa and plasma concentration. CrCL improved the PD model fit. Anti-FIIa was more sensitive to the increase in dabigatran exposure than APTT and PT in the PD model. Therefore, fixed dabigatran doses could be prescribed for patients with NVAF without adjusting for age and HDL-C. We observed an elevated bleeding tendency with higher peak and trough values of APTT, PT, and anti-FIIa. Randomized studies should be performed to evaluate the efficacy and safety of low-dose dabigatran in Chinese patients with NVAF.
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影响因子：
37.8
作者：
January CT;Wann LS;Alpert JS;Calkins H;Cigarroa JE;Cleveland JC Jr;Conti JB;Ellinor PT;Ezekowitz MD;Field ME;Murray KT;Sacco RL;Stevenson WG;Tchou PJ;Tracy CM;Yancy CW;ACC/AHA Task Force Members
通讯作者：
ACC/AHA Task Force Members
影响因子：
4
作者：
Mitchell, AM;Tom, M;Mortimer, RH
通讯作者：
Mortimer, RH
影响因子：
2.7
作者：
Okumura K;Hori M;Tanahashi N;John Camm A
通讯作者：
John Camm A
DOI：
10.2215/cjn.06870909
发表时间：
2010-06-01
影响因子：
9.8
作者：
Michels, Wieneke Marleen;Grootendorst, Diana Carina;Krediet, Raymond Theodorus
通讯作者：
Krediet, Raymond Theodorus
影响因子：
3.1
作者：
Sinigoj, Petra;Malmstrom, Rickard E.;Mavri, Alenka
通讯作者：
Mavri, Alenka