Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I, Open-Label, Randomized Study,Drugs in R&D

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Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I, Open-Label, Randomized Study
Drugs in R&D ( IF 2.2 ) Pub Date : 2022-04-12 , DOI: 10.1007/s40268-022-00388-1
Ashit Trivedi ₁ , Y-H Kiang ₁ , Robert E Saw ₁ , Guilong Charles Cheng _{1,

2} , Omar Mather ₁ , Silvia Vega ₁ , Jennifer Hellawell ₃ , Edward Lee ₁

Affiliation

Background and objective

AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects.

Methods

In a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects.

Results

Following a single oral dose of AMG 986, the geometric mean maximum observed concentration (C_max) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC_0–120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81–0.96) and 0.72 (90% CI 0.57–0.91) for AUC_0–120h and C_max, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity.

Conclusion

There was a modest 12% decrease in AUC_0–120h and a 28% decrease in C_max with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.

中文翻译：

健康成人受试者中 AMG 986 片剂和胶囊制剂的药代动力学和安全性评估：I 期、开放标签、随机研究

背景和目标

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。目前进行的 I 期研究是为了在 12 名健康受试者中评估单剂量 200 mg AMG 986 胶囊制剂相对于片剂制剂的药代动力学和安全性。

方法

在两期双向交叉设计中，符合条件的受试者以 1:1 的比例随机分配至片剂/胶囊或胶囊/片剂治疗序列；每个治疗序列持续大约 6 天，由六名受试者组成。

结果

单次口服剂量 AMG 986 后，几何平均最大观察浓度 ( C _max ) 值为 9670 ng/mL 和 6920 ng/mL，几何平均曲线下面积从时间 0 到 120 h (AUC _0–120h )片剂和胶囊的值分别为 68,000 ng*h/mL 和 59,900 ng*h/mL。胶囊/片剂比率的几何最小二乘平均值（90%置信区间[90% CI]）对于AUC 0-120h和Cmax分别为0.88（90% CI 0.81-0.96）和0.72（90% _CI 0.57-0.91 ）分别为_最大值。AMG 986 具有可接受的安全性；所有不良事件的严重程度均为 1 级或 2 级。