Dataset Information

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

ABSTRACT: Context:11?-Methyl-19-nortestosterone-17?-dodecylcarbonate (11?-MNTDC) is an orally bioavailable prodrug of 11?-methyl-19-nortestosterone (11?-MNT) with androgenic and progestational activity. Objectives:(i) Quantify 11?-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11?-MNTDC in men. Design and Setting:(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. Participants and Intervention:Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11?-MNTDC or placebo given with or without food. Main Outcome Measures:(i) In vitro 11?-MNT/11?-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. Results:11?-MNT avidly binds and activates human androgen and progesterone receptors, but 11?-MNTDC has minimal activity. Single oral doses of 11?-MNTDC were well tolerated without serious adverse events. Administration of 11?-MNTDC with food markedly increased average 11?-MNTDC and 11?-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). Conclusions:A single, oral dose of 11?-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11?-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.

SUBMITTER: Wu S

PROVIDER: S-EPMC6334268 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Wu Sherry S Yuen Fiona F Swerdloff Ronald S RS Pak Youngju Y Thirumalai Arthi A Liu Peter Y PY Amory John K JK Bai Feng F Hull Laura L Blithe Diana L DL Anawalt Bradley D BD Parman Toufan T Kim Kyuri K Lee Min S MS Bremner William J WJ Page Stephanie T ST Wang Christina C

The Journal of clinical endocrinology and metabolism 20190301 3

<h4>Context</h4>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.<h4>Objectives</h4>(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.<h4>Design and setting</h4>(i) In vitro receptor binding and transactivation studies and (ii) randomized ...[more]

PMID: 30252057

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Project description:Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 μg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 μg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.).

Dataset Information

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

Publications

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

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