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Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate in Men.
J Clin Endocrinol Metab 2019; 104(3):629-638JC

Abstract

Context

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.

Objectives

(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.

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 11β-MNTDC or placebo given with or without food.

Main Outcome Measures

(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.

Results

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).

Conclusions

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.

Authors+Show Affiliations

Department of Medicine, University of Washington, Seattle, Washington.Department of Medicine, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.Department of Medicine, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.Department of Medicine, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.Department of Medicine, University of Washington, Seattle, Washington.Department of Medicine, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.Department of Medicine, University of Washington, Seattle, Washington.Department of Medicine, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.Department of Medicine, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.Contraception Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.Department of Medicine, University of Washington, Seattle, Washington.SRI International Biosciences Division, Menlo Park, California.SRI International Biosciences Division, Menlo Park, California.Contraception Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.Department of Medicine, University of Washington, Seattle, Washington.Department of Medicine, University of Washington, Seattle, Washington.Department of Medicine, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30252057

Citation

Wu, Sherry, et al. "Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate in Men." The Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 3, 2019, pp. 629-638.
Wu S, Yuen F, Swerdloff RS, et al. Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate in Men. J Clin Endocrinol Metab. 2019;104(3):629-638.
Wu, S., Yuen, F., Swerdloff, R. S., Pak, Y., Thirumalai, A., Liu, P. Y., ... Wang, C. (2019). Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate in Men. The Journal of Clinical Endocrinology and Metabolism, 104(3), pp. 629-638. doi:10.1210/jc.2018-01528.
Wu S, et al. Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate in Men. J Clin Endocrinol Metab. 2019 Mar 1;104(3):629-638. PubMed PMID: 30252057.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate in Men. AU - Wu,Sherry, AU - Yuen,Fiona, AU - Swerdloff,Ronald S, AU - Pak,Youngju, AU - Thirumalai,Arthi, AU - Liu,Peter Y, AU - Amory,John K, AU - Bai,Feng, AU - Hull,Laura, AU - Blithe,Diana L, AU - Anawalt,Bradley D, AU - Parman,Toufan, AU - Kim,Kyuri, AU - Lee,Min S, AU - Bremner,William J, AU - Page,Stephanie T, AU - Wang,Christina, PY - 2018/07/13/received PY - 2018/09/19/accepted PY - 2019/09/24/pmc-release PY - 2018/9/27/pubmed PY - 2018/9/27/medline PY - 2018/9/26/entrez SP - 629 EP - 638 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 104 IS - 3 N2 - Context: 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. Objectives: (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. 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 11β-MNTDC or placebo given with or without food. Main Outcome Measures: (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. Results: 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). Conclusions: 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. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/30252057/Safety_and_Pharmacokinetics_of_Single-Dose_Novel_Oral_Androgen_11β-Methyl-19-Nortestosterone-17β-Dodecylcarbonate_in_Men L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2018-01528 DB - PRIME DP - Unbound Medicine ER -