Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate in Men

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 3; pp. 629 - 638
• Main Authors: Wu, Sherry, Yuen, Fiona, Swerdloff, Ronald S, Pak, Youngju, Thirumalai, Arthi, Liu, Peter Y, Amory, John K, Bai, Feng, Hull, Laura, Blithe, Diana L, Anawalt, Bradley D, Parman, Toufan, Kim, Kyuri, Lee, Min S, Bremner, William J, Page, Stephanie T, Wang, Christina
• Format: Journal Article
• Language: English
• Published: United States Copyright Oxford University Press 01.03.2019; Oxford University Press; Endocrine Society
• Subjects: Administration, Oral; Adult; Androgens; Biological Availability; Clinical s; Contraceptive Agents, Male - administration & dosage; Contraceptive Agents, Male - adverse effects; Contraceptive Agents, Male - pharmacokinetics; Dosage; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Food; Gonadotropins; Healthy Volunteers; Humans; Male; Middle Aged; Nandrolone - administration & dosage; Nandrolone - adverse effects; Nandrolone - analogs & derivatives; Nandrolone - pharmacokinetics; Pharmacokinetics; Pituitary (anterior); Progesterone; Progesterone receptors; Receptors, Androgen - metabolism; Receptors, Progesterone - metabolism; Safety; Testosterone; Young Adult
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2018-01528

11β-Methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) is an orally bioavailable prodrug of 11β-methyl-19-nortestosterone (11β-MNT) with androgenic and progestational activity. (i) Quantify 11β-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11β-MNTDC in men. (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers. Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11β-MNTDC or placebo given with or without food. (i) In vitro 11β-MNT/11β-MNTDC human receptor binding and transactivation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing. 11β-MNT avidly binds and activates human androgen and progesterone receptors, but 11β-MNTDC has minimal activity. Single oral doses of 11β-MNTDC were well tolerated without serious adverse events. Administration of 11β-MNTDC with food markedly increased average 11β-MNTDC and 11β-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05). A single, oral dose of 11β-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11β-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.