Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, NC, USA.
Receptos, a wholly owned Subsidiary of Celgene, San Diego, CA, USA.
Br J Clin Pharmacol. 2017 Oct;83(10):2179-2194. doi: 10.1111/bcp.13316. Epub 2017 Jun 10.
Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of the SARM GSK2881078.
In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0.05 mg, 0.2 mg then 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg, or placebo; in women (n = 24) they were 0.24 mg, 0.35 mg, or placebo (7 days for 0.5 mg, 14 days for other doses).
PK analysis showed dose-proportional increases in exposure and a long >100-h half-life. No significant effects on vital signs, electrocardiograms, cardiac telemetry or standard clinical laboratory studies were observed. A dose-response effect was observed on lowering both high-density lipoprotein and sex hormone-binding globulin. In females at 0.35 mg, differences from placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l and -39.1 (-48.5, -29.7) nmol l , respectively. Women showed greater sensitivity to these parameters at lower doses than men. Drug-related adverse events (AEs) were mild. One woman developed a drug rash and was withdrawn. Two men had elevated creatine phosphokinase after physical exertion during follow-up. A serious AE occurred in a subject on placebo.
These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM.
选择性雄激素受体调节剂（SARMs）可在不产生雄激素类固醇的不良反应的情况下对肌肉产生合成代谢作用。在这项首次人体研究中，我们报告了 SARM GSK2881078 的安全性、耐受性、药代动力学（PK）和药效学。
在 A 部分，健康年轻男性（n=10）接受单次研究药物剂量（0mg、0.05mg、0.1mg、0.2mg GSK2881078 或匹配安慰剂）。在 B 部分，男性重复剂量队列（n=65）为 0.05mg、0.2mg，然后为 0.08mg、0.24mg、0.48mg、0.75mg 或安慰剂；女性（n=24）为 0.24mg、0.35mg 或安慰剂（0.5mg 为 7 天，其他剂量为 14 天）。
PK 分析显示，暴露量呈剂量比例增加，半衰期长（>100 小时）。未观察到对生命体征、心电图、心脏遥测或标准临床实验室研究有显著影响。在降低高密度脂蛋白和性激素结合球蛋白方面观察到剂量反应效应。在女性 0.35mg 时，与安慰剂相比，差异分别为-0.518（95%置信区间：-0.703，-0.334）mmol/L 和-39.1（-48.5，-29.7）nmol/L。女性在较低剂量时对这些参数的敏感性大于男性。药物相关不良事件（AE）为轻度。一名女性出现药物性皮疹并被撤出。两名男性在随访期间因体力活动后肌酸磷酸激酶升高。一名安慰剂受试者发生严重 AE。
这些数据显示了具有可接受耐受性的药效学作用，并支持对这种 SARM 的进一步临床评估。
