In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins.
In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins.
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DOI：
10.1021/acsptsci.3c00095
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发表时间：
2023-09
影响因子：
6
通讯作者：
J. Yang;Sungyun Yang;Xun Gong;N. Bakh;Ge Zhang;Allison B. Wang;A. Cherrington;Michael A. Weiss;Michael S. Strano
中科院分区：
文献类型：
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作者：
J. Yang;Sungyun Yang;Xun Gong;N. Bakh;Ge Zhang;Allison B. Wang;A. Cherrington;Michael A. Weiss;Michael S. Strano
默克公司的葡萄糖响应性胰岛素（GRI）MK - 2640是同类中进入临床阶段的先驱，通过一种新型竞争清除机制（CCM）在体外和临床前研究中已显示出良好的响应性。人体中较小的药代动力学反应促使开发新的预测性计算工具，以改进如葡萄糖响应性胰岛素等治疗药物的设计。在此，我们开发并使用一种新的计算模型IM3PACT，该模型基于人类和动物模型糖调节系统的交叉部分，根据MK - 2640和普通人类胰岛素（RHI）已有的临床前和临床数据来研究CCM葡萄糖响应性胰岛素的临床转化性。模拟的多次血糖钳夹试验不仅验证了先前关于人类葡萄糖响应性清除能力不足的假设，还揭示了体内竞争特性与生理血糖范围之间同样重要的不匹配情况，而这种情况在动物中未被观察到。消除物种间差异使人类的葡萄糖依赖性葡萄糖响应性胰岛素清除率从13.0%提高到20%以上，当两个因素都得到纠正时，清除率可高达33.3%。内在清除率、效力和分布容积显然没有影响转化。分析还证实了肝脏局部的响应性药代动力学。通过对CCM葡萄糖响应性胰岛素的大型设计空间进行扫描，我们发现即使对于设计最优化的候选药物，人类的甘露糖受体生理学仍然具有局限性。总体而言，我们表明这种计算方法能够从临床前和临床数据的事后分析中提取有价值的定量和机制信息，以辅助未来的治疗发现和开发。
The glucose-responsive insulin (GRI) MK-2640 from Merck was a pioneer in its class to enter the clinical stage, having demonstrated promising responsiveness in in vitro and preclinical studies via a novel competitive clearance mechanism (CCM). The smaller pharmacokinetic response in humans motivates the development of new predictive, computational tools that can improve the design of therapeutics such as GRIs. Herein, we develop and use a new computational model, IM3PACT, based on the intersection of human and animal model glucoregulatory systems, to investigate the clinical translatability of CCM GRIs based on existing preclinical and clinical data of MK-2640 and regular human insulin (RHI). Simulated multi-glycemic clamps not only validated the earlier hypothesis of insufficient glucose-responsive clearance capacity in humans but also uncovered an equally important mismatch between the in vivo competitiveness profile and the physiological glycemic range, which was not observed in animals. Removing the inter-species gap increases the glucose-dependent GRI clearance from 13.0% to beyond 20% for humans and up to 33.3% when both factors were corrected. The intrinsic clearance rate, potency, and distribution volume did not apparently compromise the translation. The analysis also confirms a responsive pharmacokinetics local to the liver. By scanning a large design space for CCM GRIs, we found that the mannose receptor physiology in humans remains limiting even for the most optimally designed candidate. Overall, we show that this computational approach is able to extract quantitative and mechanistic information of value from a posteriori analysis of preclinical and clinical data to assist future therapeutic discovery and development.