Introduction

M8891 is a selective and reversible inhibitor of methionine aminopeptidase 2 (MetAP2). We describe translational research to define the target pharmacokinetics (PK) of M8891 and associated pharmacodynamic (PD) levels, which were used to support efficacious dose selection in humans.

Methods

In vitro and in vivo PK characteristics were investigated in animal species, and data integrated using in vitro–in vivo correlation and allometric methods to predict the clearance, volume of distribution, and absorption parameters of M8891 in humans. In parallel, inhibition of MetAP2 activity by M8891 was studied in renal cancer xenografts in mice by measuring accumulation of Met-EF1α, a substrate of MetAP2. The corresponding PD effect was described by a turnover and effect compartment model. This model was used to simulate PD at the M8891 dose showing in vivo efficacy, i.e. significant tumor growth inhibition. Simulations of M8891 PK and associated PD in humans were conducted by integrating predicted human PK parameters into the preclinical PK/PD model.

Results

The target minimum PD level associated with efficacy was determined to be 125 µg Met-EF1α per mg protein. Integrating predicted human PK parameters into the preclinical PK/PD model defined a minimal M8891 concentration at steady-state (C_trough) of 1500 ng/mL (3.9 µM) in humans as being required to produce the corresponding minimum target Met-EF1a level (125 µg per mg protein).

Conclusion

The defined target PK and PD levels supported the design of the clinical Phase Ia dose escalation study of M8891 (NCT03138538) and selection of the recommended Phase II dose.

中文翻译：

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M8891（甲硫氨酸氨基肽酶 2 的有效可逆抑制剂）的临床前药代动力学和转化药代动力学/药效学建模

介绍

M8891 是蛋氨酸氨肽酶 2 (MetAP2) 的选择性可逆抑制剂。我们描述了转化研究，以确定 M8891 的目标药代动力学 (PK) 和相关的药效学 (PD) 水平，这些水平用于支持人类有效的剂量选择。

方法

研究了动物物种的体外和体内PK 特征，并使用体外-体内相关性和异速生长方法整合数据来预测 M8891 在人体中的清除率、分布体积和吸收参数。与此同时，通过测量 Met-EF1α（MetAP2 的底物）的积累，研究了 M8891 在小鼠肾癌异种移植物中对 MetAP2 活性的抑制作用。相应的PD效应通过周转和效应室模型来描述。该模型用于模拟 M8891 剂量下的 PD，显示出体内功效，即显着的肿瘤生长抑制。通过将预测的人类 PK 参数整合到临床前 PK/PD 模型中，对人类 M8891 PK 和相关 PD 进行模拟。

结果

与疗效相关的目标最低 PD 水平确定为每毫克蛋白质 125 µg Met-EF1α。将预测的人体 PK 参数整合到临床前 PK/PD 模型中，定义了人体稳态（C_谷）的最低 M8891 浓度为 1500 ng/mL (3.9 µM)，因为需要产生相应的最低目标 Met-EF1a 水平（每毫克蛋白质 125 微克）。

结论

确定的目标 PK 和 PD 水平支持 M8891 (NCT03138538) 临床 Ia 期剂量递增研究的设计和推荐 II 期剂量的选择。