Rational Design of Glucose‐Responsive Insulin Using Pharmacokinetic Modeling,Advanced Healthcare Materials

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Rational Design of Glucose‐Responsive Insulin Using Pharmacokinetic Modeling
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2017-08-25 , DOI: 10.1002/adhm.201700601
Naveed A. Bakh ₁ , Gili Bisker ₁ , Michael A. Lee ₁ , Xun Gong ₁ , Michael S. Strano ₁

Affiliation

A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well‐developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing.

中文翻译：

使用药代动力学模型合理设计葡萄糖反应性胰岛素

葡萄糖反应性胰岛素（GRI）是一种治疗药物，可根据患者的动态葡萄糖浓度调节其效力，浓度或胰岛素剂量，从而近似正常运作的胰腺的各个方面。当前的GRI设计缺乏理论基础，基础理论设计基础参数诸如葡萄糖反应性，解离常数或效价以及体内功效。在这项工作中，提出了一种对有效GRI的相关参数空间进行数学建模的方法，并开发了将GRI性能与治疗效益联系起来的设计规则。完善的人体葡萄糖和胰岛素代谢的药代动力学模型，以及自由循环GRI的动力学模型表示，可用于确定所需的动力学参数和剂量，以实现最佳的血糖控制。该模型以最佳范围内的动力学参数检查GRI的皮下剂量，该剂量可在24小时内在规定的约束范围内成功完成血糖控制。另外，证明了该建模方法可以找到GRI参数，这些参数可以使稳定的葡萄糖水平持续到跳过一顿饭。结果为探索GRI的参数空间提供了框架，可能无需进行广泛的反复体内动物测试。

更新日期：2017-08-25

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