Using a Vancomycin PBPK Model in Special Populations to Elucidate Case-Based Clinical PK Observations.
Using a Vancomycin PBPK Model in Special Populations to Elucidate Case-Based Clinical PK Observations.
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DOI：
10.1002/psp4.12279
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Fukuda T
中科院分区：
文献类型：
--
作者：
Emoto C;Johnson TN;McPhail BT;Vinks AA;Fukuda T
几种生理因素的同时变化可能导致万古霉素的药代动力学（PK）变异性较大。本研究旨在系统地表征多种生理因素对特殊人群中观察到的万古霉素PK改变的影响。开发了万古霉素生理药代动力学（PBPK）模型作为PK模拟平台，以定量评估生理学变化对PK特征的影响。开发的模型预测了健康成人和患病患者的浓度-时间曲线。在儿科模型中实施肾脏和非肾脏消除途径的发育变化提高了万古霉素清除的可预测性。心输出量降低50%的模拟PK曲线（血浆峰浓度（Cmax），59.9 ng/mL）与旁路手术前患者中观察到的PK曲线（Cmax，55.1 ng/mL）相似。万古霉素的PBPK建模证明了其为观察到多个生理因素变化的患者中的处置改变提供机制见解的潜力。
Simultaneous changes in several physiological factors may contribute to the large pharmacokinetic (PK) variability of vancomycin. This study was designed to systematically characterize the effects of multiple physiological factors to the altered PK of vancomycin observed in special populations. A vancomycin physiologically based pharmacokinetic (PBPK) model was developed as a PK simulation platform to quantitatively assess the effects of changes in physiologies to the PK profiles. The developed model predicted the concentration‐time profiles in healthy adults and diseased patients. The implementation of developmental changes in both renal and non‐renal elimination pathways to the pediatric model improved the predictability of vancomycin clearance. Simulated PK profiles with a 50% decrease in cardiac output (peak plasma concentration (Cmax), 59.9 ng/mL) were similar to those observed in patients before bypass surgery (Cmax, 55.1 ng/mL). The PBPK modeling of vancomycin demonstrated its potential to provide mechanistic insights into the altered disposition observed in patients who have changes in multiple physiological factors.
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