Ayoub R, Page S T, Swerdloff R S, Liu P Y, Amory J K, Leung A, Hull L, Blithe D, Christy A, Chao J H, Bremner W J, Wang C
Department of Medicine, Division of Endocrinology, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
Andrology. 2017 Mar;5(2):278-285. doi: 10.1111/andr.12303. Epub 2016 Dec 1.
Dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p < 0.007) and average concentrations (p < 0.002) at the 400 mg dose, compared with the 200 mg dose. The powder formulation resulted in a lower conversion of DMAU to DMA (p = 0.027) compared with both castor oil and SEDDS formulations. DMAU in SEDDS given fasting resulted in higher serum DMA and DMAU concentrations compared to the other two formulations. Serum LH and sex hormone concentrations were suppressed by all formulations of 200 and 400 mg DMAU when administered with food, but only the SEDDS formulation was effectively suppressed serum T when given fasting. We conclude that while all three formulations of oral DMAU are effective and well tolerated when administered with food, DMAU in oil and SEDDS increased conversion to DMA, and SEDDS may have some effectiveness when given fasting. These properties might be advantageous for the application of DMAU as a male contraceptive.
二甲双氢睾酮（DMA，7α,11β - 二甲基 - 19 - 去甲睾酮）具有雄激素和孕激素活性，是男性激素避孕药的理想特性。在体内，十一酸二甲双氢睾酮（DMAU）会水解为DMA。我们之前表明，与食物一起服用的胶囊形式的单剂量口服DMAU粉末耐受性良好，且在抑制促黄体生成素（LH）和睾酮（T）方面有效，但吸收较低。我们将两种新的DMAU制剂（蓖麻油制剂和自乳化药物递送系统（SEDDS）制剂）的药代动力学和药效学与之前测试的粉末制剂进行了比较。在两个学术医疗中心，对健康成年男性志愿者口服给予DMAU。在这项双盲、安慰剂对照研究中，对于每种测试制剂，10名男性接受单剂量、递增的口服DMAU（100、200和400毫克），两名受试者接受安慰剂。所有剂量均在空腹和高脂餐后进行评估。所有三种制剂耐受性良好，生命体征、血细胞计数或血清化学指标均无临床显著变化。对于所有制剂，与200毫克剂量相比，400毫克剂量的DMA和DMAU显示出更高的最大浓度（p < 0.007）和平均浓度（p < 0.002）。与蓖麻油制剂和SEDDS制剂相比，粉末制剂导致DMAU向DMA的转化率较低（p = 0.027）。空腹服用时，SEDDS中的DMAU导致血清DMA和DMAU浓度高于其他两种制剂。与食物一起服用时，所有200毫克和400毫克DMAU制剂均能抑制血清LH和性激素浓度，但只有SEDDS制剂在空腹服用时能有效抑制血清T。我们得出结论，虽然口服DMAU的所有三种制剂与食物一起服用时均有效且耐受性良好，但油剂和SEDDS中的DMAU增加了向DMA的转化，并且SEDDS在空腹服用时可能具有一定效果。这些特性可能有利于DMAU作为男性避孕药的应用。
