A First in Human Study of the Pharmacokinetics, Safety and Food Effects of Orally Administered DMAU: A Prototype Oral Male Hormonal Contraceptive

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 554-583-Male Reproductive Endocrinology & Case Reports
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-561
Prasanth Surampudi*1, Stephanie T Page2, Ronald S. Swerdloff1, Jean Jacques S Nya-Ngatchou3, Peter Y Liu1, Peter Christenson4, John Kenneth Amory5, Andrew Leung6, Laura Hull7, Diana Lynn Blithe8, Jason Woo8, William J Bremner2 and Christina CL Wang9
1Harbor - UCLA Med Ctr and Los Angeles Biomedical Research Institute, Torrance, CA, 2University of Washington, Seattle, WA, 3Univ of Washington, Seattle, WA, 4Los Angeles Biomeidcal Research Institute at Harbor-UCLA Medical Center, Torrance, 5Univ of WA Med Ctr, Seattle, WA, 6Los Angeles Biomedical Research Insititute at Harbor-UCLA Medical Center, Torrance, 7Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, 8Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, 9Harbor - UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA
Context: Dimethandrolone Undecanoate (DMAU) is a novel androgen in development as a male hormonal contraceptive.  DMAU is not 5a-reduced and hence is prostate-sparing. DMAU is hydrolyzed to the active compound dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone) that has both androgenic and progestational activities, enhancing suppression of gonadotropins and spermatogenesis.  In preclinical studies in male rats, rabbits and monkeys, DMAU exhibited androgenic and contraceptive effects and was well tolerated when administered orally up to 125 mg/Kg/day.

Objective: To assess the safety and pharmacokinetics (PK) of single, escalating doses of oral DMAU (powder in capsule formulation) administered with and without food in healthy men.

Design, Setting, Participants and Intervention: We conducted a randomized, placebo-controlled, double-blind study in healthy men, ages 31.7±2.3 y. For each dose, 12 male volunteers received either DMAU (n=10), or placebo (n=2) at one of two participating academic medical centers. Single oral doses of DMAU were given while fasting (25 mg, 50 mg, 100 mg, 200 mg, 400 mg, and 800 mg) and (200, 400, 800 mg) with a high fat meal (50% calories from fat). Serial serum samples were collected for 24-hours following dosing. Serum DMAU and DMA were measured by LC-MS/MS (LLOQ for DMA =0.5 and DMAU=1 ng/ml).

Results: DMAU was well tolerated, without serious adverse events at any dose.  There were no clinically significant effects of DMAU on vital signs, blood counts, clinical chemistries, or electrocardiograms. When administered fasting, DMAU was detected in serum when men were given DMAU >100 mg, whereas serum DMA became detectable in all subjects only at the 800 mg DMAU dose.  In contrast, when taken with a high-fat meal, serum DMA was detectable in all subjects receiving >200 mg DMAU and showed a dose proportional increase. The table shows DMA PK after 800 mg dose (N=10).

Dose                  Cavg (ng/ml) Cmax(ng/ml) Cmin1(ng/ml) Tmax (h) Tmin1 (h)

800mg Fasting   0.9±0.2         2.7±1.1           < 0.5              3.6±1.4    8.4±3.0

800mg Fed        11.2±1.8        52.3±11.2      1.3±0.2           6.0±0.6    24.0±0

Conclusions: This first study of DMAU administration in men demonstrates that a single, oral dose of DMAU up to 800 mg is safe and well tolerated. Co-administration of oral DMAU with food greatly enhanced absorption and improved pharmacokinetics. Reformulation of oral DMAU delivery to achieve predictable, therapeutic DMA levels in both the fasting and fed states is ongoing.

Nothing to Disclose: PS, STP, RSS, JJSN, PYL, PC, JKA, AL, LH, DLB, JW, WJB, CCW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Sources of support NIH NICHD Contraceptive Clinical Trials Network Center Male Area (NO1 Contract HHSN275201000080U ) and NCATs CTSA awards to UCLA (UL1 TR000124) and University of Washington