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

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.

Trial registration: ClinicalTrials.gov NCT02754687.

Figure 1.

AR and PR binding and transactivation of 11β-MNTDC and 11β-MNT. (A) Receptor binding activity and IC₅₀ of 11β-MNTDC and 11β-MNT compared with DHT and progesterone binding to AR and PR, respectively. (B) Receptor transactivation in cell-based assays showing agonistic activity of 11β-MNTDC and 11β-MNT through AR or PR compared with DHT and progesterone, respectively.

Figure 2.

Serum concentrations of 11β-MNTDC (upper panel) and 11β-MNT (lower panel) over 24 hours after oral administration of 0, 100, 200, 400, and 800 mg 11β-MNTDC with and without a high-fat meal. The means ± SEMs were computed after log transformation and plotted after back transformation.

Figure 3.

Serum concentrations, C_avg (over 24 hours), and C_min of LH, FSH, T, and estradiol after oral administration of 0, 100, 200, 400, and 800 mg 11β-MNTDC with and without a high-fat meal.