High-Precision Control of Plasma Drug Levels Using Feedback-Controlled Dosing
High-Precision Control of Plasma Drug Levels Using Feedback-Controlled Dosing
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DOI：
10.1021/acsptsci.8b00033
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发表时间：
2018-11-09
影响因子：
--
通讯作者：
Plaxco, Kevin W.
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文献类型：
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作者：
Arroyo-Curras, Netzahualcoyotl;Ortega, Gabriel;Plaxco, Kevin W.
实际上，通过使药代动力学成为实验上可调节的参数，通过高频体内药物测量进行反馈控制给药的能力将被证明是药理学研究和临床实践的有力工具。然而，由于不能在真实的时间内并且以足够的便利性和时间分辨率测量体内药物水平，为此目的的努力在历史上受到阻碍。作为回应，我们描述了一种闭环反馈控制的递送系统，该系统使用由基于体内电化学适体（E-AB）的传感器提供的药物水平测量来每7秒调整给药速率。所得到的系统支持在多个小时内在活大鼠中维持恒定或预定义的随时间变化的血浆药物浓度曲线。对于研究人员来说，由此产生的对药物血浆浓度的高精度控制提供了前所未有的机会，以（1）绘制药代动力学和临床结果之间的关系，（2）消除受试者间和受试者内代谢变异作为混淆实验变量，（3）在动物模型中准确模拟人体药代动力学，以及（4）测量药物的药代动力学行为响应于改变的健康状况、饮食、药物-药物相互作用或其它内在和外部因素的分钟到分钟的变化。在临床上，反馈控制的药物递送将提高我们在面对大的、通常不可预测的患者内和患者间代谢变化时准确维持治疗药物水平的能力。这反过来又会提高治疗干预的有效性和安全性，特别是对于病情最严重的患者，因为对他们来说，代谢变异性最高，治疗错误的余地最小。
By, in effect, rendering pharmacokinetics an experimentally adjustable parameter, the ability to perform feedback-controlled dosing informed by high-frequency in vivo drug measurements would prove a powerful tool for both pharmacological research and clinical practice. Efforts to this end, however, have historically been thwarted by an inability to measure in vivo drug levels in real time and with sufficient convenience and temporal resolution. In response, we describe a closed-loop, feedback-controlled delivery system that uses drug level measurements provided by an in vivo electrochemical aptamer-based (E-AB) sensor to adjust dosing rates every 7 s. The resulting system supports the maintenance of either constant or predefined time-varying plasma drug concentration profiles in live rats over many hours. For researchers, the resultant high-precision control over drug plasma concentrations provides an unprecedented opportunity to (1) map the relationships between pharmacokinetics and clinical outcomes, (2) eliminate inter- and intrasubject metabolic variation as a confounding experimental variable, (3) accurately simulate human pharmacokinetics in animal models, and (4) measure minute-to-minute changes in a drug's pharmacokinetic behavior in response to changing health status, diet, drug-drug interactions, or other intrinsic and external factors. In the clinic, feedback-controlled drug delivery would improve our ability to accurately maintain therapeutic drug levels in the face of large, often unpredictable intra- and interpatient metabolic variation. This, in turn, would improve the efficacy and safety of therapeutic intervention, particularly for the most gravely ill patients, for whom metabolic variability is highest and the margin for therapeutic error is smallest.