SINGLE, ESCALATING DOSE PHARMACOKINETICS, SAFETY, AND FOOD EFFECTS OF A NEW ORAL ANDROGEN 11 beta-METHYL-19-NORTESTOSTERONE 17 beta-DODECYLCARBONATE IN MAN: A POTENTIAL ORAL MALE HORMONAL CONTRACEPTIVE

ester (DMAU) are modified testosterone (T) derivatives that have androgenic and progestational actions, suppress gonadotropins, maintain androgenic effects and inhibit spermatogenesis in pre-clinical studies. A first-in-men study showed that single oral DMAU doses of 200–800 mg, were well tolerated and reversibly suppressed serum LH and T. We assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of 28 days of daily oral DMAU in healthy young men. Methods used A phase 1b, double blind study was conducted at 2 academic medical centres. Healthy men (18–50 y) were randomised to receive either daily oral placebo or 100/200/ 400 mg of DMAU with food in 1 of 2 unique formulations – castor oil/benzyl benzoate (C) or powder in capsule (P). Subjects underwent 24 hour PK studies with hourly vitals, serial blood DMAU/DMA and hormone measurements on days 1 and 28 and twice weekly ambulatory visits for safety labs, hormones and drug levels. The primary outcomes were safety measures (vitals, hematocrit, liver function tests, serum lipids, EKGs and adverse events). Secondary outcomes were PK profiles and PD effects – suppression of LH, FSH and T, sexual function (per validated psychosexual diary) and mood (PHQ9) throughout the study. Summary of results 83 subjects completed the study. There were neither serious adverse events nor significant changes in serial safety measures, mood or sexual function in any group. 9 subjects reported decreased libido (8 drug, 1 placebo) and 8 reported acne (5 drug, 3 placebo); all resolved by study conclusion. A dose-related Cavg was seen at day 28 for both serum concentrations of DMAU (p<0.001) and DMA (p<0.001). All active treatment groups reduced serum T into the hypogonadal range (day 28 median Cavg 13.4 ng/dL, IQR 7.6–72.1 ng/dL). All subjects in the P400mg group And 12/13 subjects in the C400mg group Achieved suppression of both LH and FSH to <1 IU/L. Conclusions Daily oral administration of DMAU for 28 days in young healthy men is well tolerated. Doses of 400 mg suppress serum T to near castrate levels and maximally suppress serum LH and FSH. These promising results support further development of DMAU as a single agent oral male contraceptive pill.