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Safety, tolerability, pharmacokinetics, and pharmacodynamics of macimorelin in healthy adults: Results of a single-dose, randomized controlled study.
Growth Hormone and IGF Research ( IF 1.6 ) Pub Date : 2020-04-15 , DOI: 10.1016/j.ghir.2020.101321
Beate Klaus 1 , Richard Sachse 2 , Nicola Ammer 2 , Nicky Kelepouris 3 , Vlady Ostrow 3
Affiliation  

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 (Cmax) of macimorelin in plasma, time to Cmax (tmax), and terminal elimination half-life (t1/2). 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 Cmax showed less than dose-proportional increases following administration of 0.5 and 1.0 mg/kg. Mean t1/2 was 3.51 h for macimorelin 0.5 and 1.0 mg/kg and 8.29 h for macimorelin 2.0 mg/kg; median tmax occurred at 0.5 to 0.75 h. GH levels increased after dosing, with a tmax of 0.75 h to 1.0 h. Mean GH Cmax 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:

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。

更新日期:2020-04-15
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