Objective

Macimorelin is an orally active ghrelin receptor agonist indicated for the diagnosis of adult growth hormone (GH) deficiency in the United States. This phase 1 study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of macimorelin (including a supratherapeutic dose to be used in a thorough QT trial) in healthy adults.

Design

Participants were randomized to receive macimorelin 0.5, 1.0, or 2.0 mg/kg or placebo in 1 of 3 sequential ascending-dose cohorts. Blood samples for pharmacokinetic and pharmacodynamic assays were collected pre-dose and at specified time points over a 24-h period. Pharmacokinetic parameters assessed included area under the concentration-time curve (AUC), maximum concentration (C_max) of macimorelin in plasma, time to C_max (t_max), and terminal elimination half-life (t_1/2). Pharmacodynamic assessments evaluated levels of GH, adrenocorticotropic hormone, thyroid-stimulating hormone, cortisol, and prolactin. Safety was assessed based on treatment-emergent adverse events (TEAEs), vital signs, 12‑lead electrocardiograms, and laboratory parameters.

Results

A total of 28 healthy adults were enrolled and completed the study. Macimorelin AUC and C_max showed less than dose-proportional increases following administration of 0.5 and 1.0 mg/kg. Mean t_1/2 was 3.51 h for macimorelin 0.5 and 1.0 mg/kg and 8.29 h for macimorelin 2.0 mg/kg; median t_max occurred at 0.5 to 0.75 h. GH levels increased after dosing, with a t_max of 0.75 h to 1.0 h. Mean GH C_max was similar with the macimorelin 0.5- and 1.0-mg/kg doses (31.9 and 37.8 ng/mL, respectively) and was ~50% lower with macimorelin 2.0 mg/kg (18.4 ng/mL). Transient increases were observed in adrenocorticotropic hormone, cortisol, and prolactin, which were not dose related. A total of 19 TEAEs were reported in 35.7% (10/28) of participants; all TEAEs were mild or moderate and resolved. A total of 12 drug-related TEAEs were reported in 8 participants. Headache was the most common drug-related TEAE. All doses of macimorelin prolonged mean QTcF by 10 to 11 ms. There were no clinically meaningful changes in vital signs or laboratory parameters.

Conclusions

Single-dose administration of macimorelin 0.5 to 2.0 mg/kg was well tolerated. Macimorelin exposure was less than dose-proportional over the dose range studied. Administration of macimorelin stimulated GH production, with the greatest increases observed in the macimorelin 0.5- and 1.0-mg/kg groups.

中文翻译：

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Macimorelin在健康成人中的安全性，耐受性，药代动力学和药效学：单剂量随机对照研究的结果。

目的

Macimorelin是一种口服活性Ghrelin受体激动剂，在美国可用于诊断成人生长激素（GH）缺乏症。这项1期研究评估了健康成年人中单剂量递增剂量的Macimorelin（包括用于全面QT试验的超治疗剂量）的安全性，耐受性，药代动力学和药效学。

设计

在3个连续的递增剂量队列中，有1个参与者随机接受Macimorelin 0.5、1.0或2.0 mg / kg或安慰剂。在给药前和24小时内的指定时间点采集用于药代动力学和药效学测定的血样。评估的药代动力学参数包括浓度-时间曲线（AUC）下的面积，血浆中Macimorelin的最大浓度（C _max），达到C _max的时间（t _max）和终末消除半衰期（t _1/2））。药效学评估评估了GH，促肾上腺皮质激素，促甲状腺激素，皮质醇和催乳激素的水平。根据治疗紧急不良事件（TEAE），生命体征，12导联心电图和实验室参数评估安全性。

结果

共有28名健康成人参加并完成了研究。施用0.5和1.0 mg / kg后，Macimorelin AUC和C _max显示小于剂量比例的增加。对于Macimorelin 0.5和1.0 mg / kg，平均t _1/2为3.51 h；对于Macimorelin 2.0 mg / kg，平均t _1/2为8.29 h。中值t _max在0.5至0.75h发生。给药后GH水平增加，_最大0.75h至1.0h。平均GH C _max与Macimorelin 0.5和1.0 mg / kg剂量（分别为31.9和37.8 ng / mL）相似，而Macimorelin 2.0 mg / kg（18.4 ng / mL）则降低约50％。促肾上腺皮质激素，皮质醇和催乳激素的瞬时增加与剂量无关。35.7％（10/28）的参与者报告了19种TEAE。所有TEAE均为轻度或中度并已消退。在8位参与者中，共报告了12种与药物相关的TEAE。头痛是与药物相关的最常见的TEAE。Macimorelin的所有剂量均将平均QTcF延长10至11 ms。生命体征或实验室参数没有临床上有意义的变化。

结论

Macimorelin 0.5至2.0 mg / kg的单剂量给药耐受性良好。在研究的剂量范围内，Macimorelin的暴露量小于比例剂量。施用Macimorelin刺激了GH的产生，在Macimorelin 0.5和1.0 mg / kg组中观察到最大的增加。