Despite considerable progress, development of glucose-responsive insulins (GRIs) still largely depends on empirical knowledge and tedious experimentation—especially on rodents. To assist the rational design and clinical translation of the therapeutic, we present a Pharmacokinetic Algorithm Mapping GRI Efficacies in Rodents and Humans (PAMERAH) built upon our previous human model. PAMERAH constitutes a framework for predicting the therapeutic efficacy of a GRI candidate from its user-specified mechanism of action, kinetics, and dosage, which we show is accurate when checked against data from experiments and literature. Results from simulated glucose clamps also agree quantitatively with recent GRI publications. We demonstrate that the model can be used to explore the vast number of permutations constituting the GRI parameter space and thereby identify the optimal design ranges that yield desired performance. A design guide aside, PAMERAH more importantly can facilitate GRI’s clinical translation by connecting each candidate’s efficacies in rats, mice, and humans. The resultant mapping helps to find GRIs that appear promising in rodents but underperform in humans (i.e., false positives). Conversely, it also allows for the discovery of optimal human GRI dynamics not captured by experiments on a rodent population (false negatives). We condense such information onto a “translatability grid” as a straightforward, visual guide for GRI development.

中文翻译：

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连接啮齿动物和人类药代动力学模型以设计和转化葡萄糖反应性胰岛素


尽管取得了相当大的进展，葡萄糖反应性胰岛素（GRI）的开发仍然在很大程度上取决于经验知识和繁琐的实验——尤其是啮齿类动物。为了帮助治疗的合理设计和临床转化，我们提出了一种建立在我们之前的人体模型基础上的药代动力学算法，映射 GRI 在啮齿动物和人类中的功效 (PAMERAH)。 PAMERAH 构成了一个框架，用于根据用户指定的作用机制、动力学和剂量来预测 GRI 候选药物的治疗效果，我们在与实验和文献数据进行检查时证明该框架是准确的。模拟葡萄糖钳的结果在数量上也与最近的 GRI 出版物一致。我们证明该模型可用于探索构成 GRI 参数空间的大量排列，从而确定产生所需性能的最佳设计范围。抛开设计指南不谈，PAMERAH 更重要的是可以通过将每个候选药物在大鼠、小鼠和人类中的功效联系起来，促进 GRI 的临床转化。由此产生的映射有助于找到在啮齿类动物中表现良好但在人类中表现不佳（即误报）的 GRI。相反，它还可以发现啮齿类动物实验中未捕获的最佳人类 GRI 动态（假阴性）。我们将这些信息浓缩到“可翻译性网格”中，作为 GRI 开发的简单直观指南。