Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients
Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients
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卡泊芬净对普通患者、重症监护病房患者和肝功能不全患者的基于全身生理学的药代动力学
DOI：
10.1038/aps.2017.176
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发表时间：
2018-05
影响因子：
8.2
通讯作者：
Dong YL
中科院分区：
文献类型：
--
作者：
Yang Qian-ting;Zhai Ya-jing;Chen Lu;Zhang Tao;Yan Yan;Meng Ti;Liu Lei-chao;Dong Ya-lin;Chen Li-mei;Wang Xue;Dong YL
卡泊芬净是一种棘白菌素类抗真菌药物，被许可作为一线治疗中重度疾病或近期暴露于唑类药物的侵袭性念珠菌病。本研究建立了基于全身生理学的药代动力学（WB-PBPK）模型预测卡泊芬净的药代动力学（PK），并结合蒙特卡罗模拟（MCS）优化卡泊芬净在不同类型患者中的临床给药方案。建立了卡泊芬净的WB-PBPK模型，并使用来自4项既往试验的原始数据进行了验证，这些试验包括普通患者、Child-Pugh B的重症监护室（ICU）患者、接受连续性肾脏替代治疗的ICU患者以及轻度和中度肝功能不全（HI）患者。MCS用于优化这些患者的卡泊芬净临床剂量方案。累积缓解分数（CFR）值≥ 90%被认为是实现最佳经验治疗的最小值。WB-PBPK模型的模拟结果与所有试验的观测值吻合良好。对于普通和ICU患者，卡泊芬净70/50 mg的AUC和Cmax随体重（BW）的增加而降低，且变化较大。MCS显示所有普通患者均达到CFR≥ 90%，无论BW如何。但并非所有体重较高（≥ 70 kg）的ICU患者都能达到CFR≥ 90%。与普通患者的标准剂量方案相比，在ICU Child-Pugh B患者中，卡泊芬净70/35 mg的AUC和Cmax显著降低，但在中度HI Child-Pugh B患者中，AUC和Cmax相似。卡泊芬净的WB-PBPK模型能够正确预测所有人群的PK。结合WB-PBPK模型和MCS可成功优化所有患者人群的卡泊芬净临床给药方案。
Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of≥ 90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥ 90% regardless of BW. But not all ICU patients with higher BW (≥ 70 kg) could achieve CFR≥ 90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.
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影响因子：
4.2
作者：
Kofla G;Ruhnke M
通讯作者：
Ruhnke M
影响因子：
2.1
作者：
C. Vorwerk;S. Tuchen;F. Streit;L. Binder;W. Hofmüller;W. Behrens-Baumann
通讯作者：
C. Vorwerk;S. Tuchen;F. Streit;L. Binder;W. Hofmüller;W. Behrens-Baumann
影响因子：
3.7
作者：
Felix Stader;Gudrun Wuerthwein;A. Groll;J. Vehreschild;O. Cornely;G. Hempel
通讯作者：
Felix Stader;Gudrun Wuerthwein;A. Groll;J. Vehreschild;O. Cornely;G. Hempel
影响因子：
2.5
作者：
M. Rodríguez-Hernández;Maite Ruiz-Pérez De Pipaón;M. Márquez-Solero;P. Martín-Rico;Juan José Castón-Osorio;F. Guerrero-Sánchez;E. Vidal-Verdú;C. García-Figueras;A. del Arco-Jiménez;J. Rodríguez-Baño;E. Martín-Mazuelos;J. M. Cisneros-Herreros
通讯作者：
M. Rodríguez-Hernández;Maite Ruiz-Pérez De Pipaón;M. Márquez-Solero;P. Martín-Rico;Juan José Castón-Osorio;F. Guerrero-Sánchez;E. Vidal-Verdú;C. García-Figueras;A. del Arco-Jiménez;J. Rodríguez-Baño;E. Martín-Mazuelos;J. M. Cisneros-Herreros
影响因子：
4.9
作者：
Weiler, Stefan;Seger, Christoph;Bellmann, Romuald
通讯作者：
Bellmann, Romuald