Background and Objective

AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects.

Methods

This was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg.

Results

Following oral administration, median time to maximum observed plasma concentration (t_max) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t_½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (C_max) and AUC_∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity.

Conclusion

AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.

中文翻译：

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评估 AMG 986 在健康日本受试者中的药代动力学、安全性和耐受性的 I 期、开放标签、单剂量研究

背景与目的

AMG 986 是一种一流的新型 apelin 受体小分子激动剂，最初开发用于治疗心力衰竭 (HF) 患者。此前，AMG 986 的首次人体研究是在健康和 HF 受试者中进行的；然而，AMG 986 并未在日本受试者中进行评估。

方法

这是一项 I 期、开放标签、单剂量、单中心研究，旨在评估 AMG 986 200 mg 和 400 mg 在 12 名健康日本受试者中的安全性和药代动力学 (PK)。六名受试者接受了 AMG 986 200 毫克，六名受试者接受了 AMG 986 400 毫克。

结果

口服给药后，AMG 986 200 mg 和 400 mg 组达到最大观察到的血浆浓度 ( t _max ) 的中位时间为 1.0 小时，平均终末半衰期 ( t _½ ) 分别为 15.1 小时和 17.6 小时。当比较 AMG 986 200 mg 和 400 mg 组时，对于 2 倍的剂量增加，观察到的最大观察血浆浓度 ( C _max ) 和 AUC _∞分别高 1.33 倍和 1.18 倍。AMG 986 表现出可接受的安全性和耐受性；所有不良事件的严重程度均较轻。

结论

AMG 986 暴露随着剂量增加而增加，并且增加小于健康日本受试者的剂量比例。本研究结果可促进 AMG 986 用于治疗日本心衰患者的后续临床开发。