Safety, pharmacokinetics and pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and postmenopausal women

  • Br J Clin Pharmacol. 2017 Oct;83(10):2179-2194. doi: 10.1111/bcp.13316.
Richard V Clark  1 ,  Ann C Walker  1 ,  Susan Andrews  1 ,  Philip Turnbull  2 ,  Jeffrey A Wald  3 ,  Mindy H Magee  4
Affiliations
  • 1. Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, NC, USA.
  • 2. Receptos, a wholly owned Subsidiary of Celgene, San Diego, CA, USA.
  • 3. qPharmetra, LLC, Cary, NC, USA.
  • 4. Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, PA, USA.
PMID: 28449232 DOI: 10.1111/bcp.13316
Abstract

Aim: 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.

Methods: 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).

Results: 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-1 and -39.1 (-48.5, -29.7) nmol l-1 , 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 One woman developed a drug rash and was withdrawn.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.

Conclusions: These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM.

Keywords
biomarkers; drug development; pharmacodynamics; pharmacokinetics.
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