The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men

Journals of Gerontology - Series A Biological Sciences and Medical Sciences

Volumn 68, Issue 1, 2013, Pages 87-95

  Basaria, Shehzad ^a   Collins, Lauren ^a   Dillon, E Lichar ^b   Orwoll, Katie ^a   Storer, Thomas W ^a   Miciek, Renee ^a   Ulloor, Jagadish ^a   Zhang, Anqi ^a   Eder, Richard ^a   Zientek, Heather ^c   Gordon, Gilad ^c   Kazmi, Syed ^c   Sheffield Moore, Melinda ^b   Bhasin, Shalender ^a  

^a BOSTON MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS MEDICAL BRANCH   (United States)

^c LIGAND PHARMACEUTICALS INC   (United States)

Author keywords

Cachexia; Function promoting anabolic therapies; Sarcopenia; SARMs; Selective androgen receptor modulators

Indexed keywords

ANDROGEN; ANDROGEN RECEPTOR; AR PROTEIN, HUMAN; LIPID; MUSCLE PROTEIN; SEX HORMONE; TESTOSTERONE;

ADULT; ANTIBODY SPECIFICITY; ARTICLE; BIOSYNTHESIS; BLOOD; BODY COMPOSITION; BODY WEIGHT; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFECT; HUMAN; MALE; MIDDLE AGED; MUSCLE STRENGTH; ORAL DRUG ADMINISTRATION; PROSTATE; RANDOMIZED CONTROLLED TRIAL;

ADMINISTRATION, ORAL; ADULT; ANDROGENS; BODY COMPOSITION; BODY WEIGHT; DOUBLE-BLIND METHOD; GONADAL STEROID HORMONES; HUMANS; LIPIDS; MALE; MIDDLE AGED; MUSCLE PROTEINS; MUSCLE STRENGTH; ORGAN SPECIFICITY; PROSTATE; RECEPTORS, ANDROGEN; TESTOSTERONE; YOUNG ADULT;

EID: 84871856095     PISSN: 10795006     EISSN: 1758535X     Source Type: Journal    
DOI: 10.1093/gerona/gls078     Document Type: Article

References (40)

1. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev. 1999;107:123-136.
2. Roy TA, Blackman MR, Harman SM, Tobin JD, Schrager M, Metter EJ. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab. 2002;283:E284-E294.
3. Melton LJ III, Khosla S, Crowson CS, O'Connor MK, O'Fallon WM, Riggs BL. Epidemiology of sarcopenia. J Am Geriatr Soc. 2000;48: 625-630.
4. Bassey EJ, Fiatarone MA, O'Neill EF, Kelly M, Evans WJ, Lipsitz LA. Leg extensor power and functional performance in very old men and women. Clin Sci (Lond). 1992;82:321-327.
5. Lexell J, Downham D, Sjostrom M. Distribution of different fibre types in human skeletal muscles. A statistical and computational study of the fibre type arrangement in m. vastus lateralis of young, healthy males. J Neurol Sci. 1984;65:353-365.
6. Orwoll E, Lambert LC, Marshall LM, et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med. 2006;166:2124-2131.
7. Morely JE, Thomas DR. Cachexia: new advances in the management of wasting diseases. J Am Med Dir Assoc. 2006;9(4):205-210.
8. Bhasin S, Calof OM, Storer TW, et al. Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Practice Endocrinol Metab. 2006; 2:146-159.
9. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335:1-7.
10. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95:639-650.
11. Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab. 2005;90:1502-1510.
12. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85: 2670-2677.
13. Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005;90:678-688.
14. Storer TW, Magliano L, Woodhouse L, et al. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab. 2003;88:1478-1485.
15. Travison TG, Basaria S, Storer TW, et al. Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci. 2011;66:1090-1099.
16. Narayanan R, Mohler ML, Bohl CE, Miller DD, Dalton JT. Selective androgen receptor modulators in preclinical and clinical development. Nucl Recept Signal. 2008;6e010.
17. Dalton JT, Barnette KG, Bohl CE, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2:153-161.
18. Miner JN, Chang W, Chapman MS, et al. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocrinology. 2007;148: 363-373.
19. Schmidt A, Kimmel DB, Bai C, et al. Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology. J Biol Chem. 2010;285:17054-17064.
20. LeBrasseur NK, Bhasin S, Miciek R, Storer TW. Tests of muscle strength and physical function: reliability and discrimination of performance in younger and older men and older men with mobility limitations. J Am Geriatr Soc. 2008;56:2118-2123.
21. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363:109-122.
22. Wolfe RR. Radioactive and Stable Isotope Tracers in Biomedicine. Principles and Practice of Kinetic Analysis. New York, NY: Wiley-Liss; 1992.
23. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spec-trometry in a community-based sample of healthy nonobese young men in the framingham heart study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011;96:2430-2439.
24. Mazer NA. A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: with illustrative examples from male and female populations. Steroids. 2009;74:512-519.
25. Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev. 2003;24:183-217.
26. Schroeder ET, Singh A, Bhasin S, et al. Effects of an oral androgen on muscle and metabolism in older, community-dwelling men. Am J Physiol Endocrinol Metab. 2003;284:E120-E128.
27. Thompson PD, Cullinane EM, Sady SP, Chenevery C, Saritelli AL, Sady MA. Contrasting effects of testosterone and stanozolol on serum lipoprotein levels. JAMA. 1989;261:1165-1168.
28. von Eckardstein A, Nofer JR, Assmann G. HDL and coronary heart disease: role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2001;20:13.
29. von Eckardstein A, Assmann G. Prevention of coronary heart disease by raising of HDL cholesterol? Curr Opin Lipidol. 2000;11:627-663.
30. Tang J, Srivastava RAK, Krul E S, et al. In vivo regulation of apolipo-protein A-I gene expression by estradiol and testosterone occurs by different mechanisms in inbred strains of mice. J Lipid Res. 1991;32: 1571-1585.
31. Krieger M. Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI. Annu Rev Biochem. 1999;68:523-555.
32. Langer C, Gansz B, Goepfert C, et al. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem Biophys Res Commun. 2002;296:1051-1057.
33. Glueck CJ, Gartside P, Fallat RW, Mendoza S. Effect of sex hormones on protamine inactivated and resistant postheparin plasma lipase. Metabolism. 1976;25:625-630.
34. Sinha-Hikim I, Artaza J, Woodhouse L, et al. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab. 2002;283: E154-E164.
35. Ibebunjo C, Eash JK, Li C, Ma Q, Glass DJ. Voluntary running, skeletal muscle gene expression, and signaling inversely regulated by orchi-dectomy and testosterone replacement. Am J Physiol Endocrinol Metab. 2011;300:E327-E340.
36. Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol. 1995;269(5 Pt 1):E820-E826.
37. Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab. 2002;282: E601-E607.
38. Sinha-Hikim I, Roth SM, Lee MI, Bhasin S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab. 2003;285:E197-E205.
39. Singh R, Artaza JN, Taylor WE, Gonzalez-Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003;144:5081-5088.
40. Serra C, Bhasin S, Tangherlini F, et al. The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle. Endocrinology. 2011;152:193-206.