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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2018 Sep 24;104(3):629–638. doi: 10.1210/jc.2018-01528

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

Sherry Wu 1,#, Fiona Yuen 2,#, Ronald S Swerdloff 2, Youngju Pak 2, Arthi Thirumalai 1, Peter Y Liu 2, John K Amory 1, Feng Bai 2, Laura Hull 2, Diana L Blithe 3, Bradley D Anawalt 1, Toufan Parman 4, Kyuri Kim 4, Min S Lee 3, William J Bremner 1, Stephanie T Page 1,#, Christina Wang 2,✉,#
PMCID: PMC6334268  PMID: 30252057

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.

Single oral doses up to 800 mg of 11β-MNTDC are well tolerated and resulted in increases in serum 11β-MNT (an androgen with progestational activity) and suppression of testosterone in healthy men.

The global rate of unintended pregnancy is high at 40%, indicating a large unmet need for contraception (1). Despite an array of female contraceptive choices, reversible male contraceptive methods remain limited. Condoms and coitus interruptus have high user failure rates and are not acceptable to many couples (2). Vasectomy requires a surgical procedure, and although sometimes reversible by a second surgical procedure, success is not guaranteed. Reversible, hormone-based male contraceptives in clinical development rely upon inhibition of the hypothalamic-pituitary-gonadal axis by exogenous sex steroids, resulting in reversible suppression of spermatogenesis with a goal to provide optimal androgen effects while suppressing intratesticular testosterone (T) production and spermatogenesis in men (3, 4). Prior studies have shown that intratesticular T levels comparable with serum T levels are not sufficient to support normal spermatogenesis, such that normal serum levels of T can be maintained without stimulating spermatogenesis in the testes (5, 6).

The World Health Organization–sponsored hormonal contraceptive efficacy trials in the 1990s demonstrated the effectiveness of weekly T enanthate injections for contraception without substantial safety concerns (7–9). T-only regimens require supraphysiologic doses of T for contraceptive efficacy. Combining a progestin with T enhances the onset and rate of spermatogenic suppression and allows for more physiologic T dosages (10–12).

Data suggest men across cultures may prefer a “male pill” over other forms of contraception (13, 14). Currently available oral T undecanoate (TU) formulations are safe but require more than once-daily administration and lack efficacy in suppression of spermatogenesis (15). Thus, novel, orally bioavailable, synthetic 19-nortestosterone derivatives with both androgenic and progestational activities are being developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development as potential male hormonal contraceptives.

11β-Methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) is de-esterified in vivo to release its active metabolite, 11β-methyl-19-nortestosterone (11β-MNT) (16). 11β-MNT has structural homology with dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone), a similar prototype male hormonal contraceptive, but has only one methyl group in the 11β position (16). Both dimethandrolone undecanoate (DMAU) and 11β-MNTDC have androgenic activity in animal models (17). Rabbit studies have shown that 11β-MNTDC is not hepatotoxic compared with other androgens with progestational activities (18), and studies in rodents and monkeys of 11β-MNTDC, DMAU and 7α-methyl-19-nortestosterone have shown no indication of hepatotocixity.

We hypothesized that, given its structural homology with DMA, 11β-MNT would have both androgenic and progestational properties in vitro and in vivo and that oral administration of the prodrug 11β-MNTDC would be safe and well tolerated in men. We examined androgen receptor (AR) and progesterone receptor (PR) binding and human cell-based transactivation activities of 11β-MNT and 11β-MNTDC in vitro. We then assessed the safety, tolerability, and pharmacokinetics of single escalating oral doses of 11β-MNTDC up to 800 mg in healthy men.

Methods and Research Participants

In vitro androgen and progesterone receptor activity

11β-MNT and 11β-MNTDC were tested in receptor binding assays. AR and PR were added to novel, tight-binding, selective ligands tagged with a fluorescent molecule, to form a receptor-ligand complex with a high polarization value. This complex was then added to individual test article samples in 96-well plates. Competitors displaced the fluorescent ligand from the complex, resulting in a low polarization value. The shift in polarization value in the presence of test articles was used to determine the relative affinity of test articles for the receptor.

AR binding activity was assessed using rat AR ligand binding domain tagged with His and glutathione S-transferase (GST) [AR-LBD (His-GST)] and the novel, tight-binding, selective fluorescent androgen ligand Fluormone AL Green (Invitrogen, Carlsbad, CA). PR binding activity was assessed using human PR ligand binding domain tagged with GST [PR-LBD (GST)] and the novel, tight-binding, selective fluorescent progesterone ligand Fluormone PL Green. Estrogen receptor (ER) binding activity was assessed using insect cell–expressed, full-length, untagged, human ERα and the novel, tight-binding, fluorescent estrogen ligand Fluormone ES2. Glucocorticoid receptor (GR) binding activity was assessed using insect cell–expressed, full-length, untagged, human GR and a novel, tight-binding, selective fluorescent ligand Fluormone GS1. The preparation of reagents and test procedures were performed according to the manufacturer’s instructions (Invitrogen). The plates were covered to protect the reagents from light and incubated at 20°C to 25°C for 48 hours. The fluorescence polarization of the samples was measured with 485-nm excitation and 530-nm emission interference filters.

Transactivation activity assay

Transactivation activities of AR and PR were assessed using the luciferase assays performed in the high-throughput screening 96-well format. AR and PR were expressed in HEC-1-B (human endometrial adenocarcinoma) and HEK-293 (human embryonic kidney) cells (both from ATCC, Manassas, VA) via transient or stable transfection of expression vectors (pEZ-AR and pEZ-PR, respectively), along with the luciferase reporter vector (MMTV-Luc). MMTV-Luc, the reporter gene construct consisting of murine mammary tumor virus long terminal repeat, contains hormone response elements that regulate the expression of a luciferase reporter gene in response to activation of AR or PR. Reference and test article compounds were serially diluted in 100% ethanol in the range of 10 mM to 1 pM. Cells expressing each receptor and MMTV-Luc were treated with the reference and test articles and incubated at 37°C in 5% CO2 for 22 to 26 hours. At the end of this period, the luciferase activity of each well was measured using the luciferase assay system according to the manufacturer’s instructions (Promega, Madison, WI). EC50/IC50 values were generated by fitting data from the luciferase reporter assay by nonlinear regression function.

Clinical study in men

We conducted a phase I multicenter, double-blind, randomized, controlled, single-dose, dosage-escalating study of oral 11β-MNTDC in healthy men.

Research participants

Healthy men ages 18 to 50 years were recruited. In brief, subjects were required to have no chronic illness, a body mass index <33 kg/m2, normal physical examination, and normal laboratory tests, including blood count, chemistry panel, liver enzymes, lipid panel (total cholesterol <220 mg/dL and triglycerides <200 mg/dL), and ECG (16). Participants were asked to abstain from alcohol, grapefruit juice, and medications during the study. This trial was registered at www.clinicaltrials.gov as NCT02754687 and performed at two sites, Los Angeles Biomedical Research Institute at the Harbor-UCLA Medical Center (LA BioMed), Torrance, California, and the University of Washington, Seattle, Washington. The study was approved by the respective institutional review boards. All participants provided written informed consent before any study procedures.

Study medications

The 11β-MNTDC was manufactured by Evestra, Inc. (San Antonio, TX) under Good Manufacturing Practices conditions. 11β-MNTDC capsules were filled at SRI International (Menlo Park, CA) as 100 mg in castor oil/benzyl benzoate (70:30, volume/volume). Placebo capsules, containing castor oil and benzyl benzoate, were filled at QS Pharma (Boothwyn, PA). Capsules containing active drug were identical in appearance to capsules containing placebo.

Study design

Following screening, 12 participants were enrolled. For each dose, 10 were randomized to receive active drug and 2 placebo, with the participants on placebo rotating randomly at each dose escalation. Randomization was performed by a statistician (Y.P.) who was not part of the study team. The participants received 100 mg, 200 mg, 400 mg, or 800 mg 11β-MNTDC orally while fasting for at least 8 hours and, on a separate occasion, after consuming a standardized breakfast containing 50% fat and 800 to 1000 calories. Subjects were confined to a clinical research unit for 24 hours after each dose, during which blood pressure and heart rate were checked hourly. ECG was performed 4 to 6 and 24 hours after dosing. Blood samples for safety laboratory tests, including a complete blood count, comprehensive metabolic panel, liver enzymes, and a lipid panel, were collected immediately prior to each dose and repeated 24 hours and 7 days after each dose and the participants were assessed for any adverse events. Subjects exited the study after serum hormones had returned to the reference range and all safety laboratory parameters were normal.

Serum concentrations of 11β-MNTDC and 11β-MNT were measured 30 minutes before dosing and 1, 2, 4, 6, 8, 12, 18, and 24 hours and 7 days following capsule administration. Drug concentrations were measured 48, 72, and 96 hours following the 800-mg fed dose. Serum hormones [total and free T, LH, FSH, and estradiol (E2)] were measured at 30 minutes predose and at 0, 4, 8, 12, 18, and 24 hours after dosing and sex hormone binding globulin (SHBG) once during the 24-hour period.

For each dosage escalation, all participants were studied first with the fasting dose and, ∼1 to 2 weeks later, the fed dose. Participants were monitored for adverse events before and after each dose. Investigators reviewed all safety data within 24 hours and with the medical monitor weekly. Dose escalation occurred after safety review of the data from all participants for both fasting and fed dosing at each dose.

Analytical methods

Safety laboratory tests were done at each study site’s local certified laboratory. All hormones were measured by the Endocrine and Metabolic Research Laboratory at LA BioMed using validated methods. Serum T, 11β-MNTDC, and 11β-MNT concentrations were measured by liquid chromatography–tandem mass spectrometry after solid-phase extraction in an assay developed specifically for this study. The T assay was modified from that previously developed by the LA BioMed laboratory (19) because 11β-MNT interfered with T quantification. The intra-assay and interassay precision were <13% for the three compounds. The accuracy ranged from 95% to 110%, spanning different concentrations within the relevant concentrations for each compound. The lower limits of quantification for T, 11β-MNTDC, and 11β-MNT were 2 ng/dL, 2 ng/mL and 0.5 ng/mL, respectively. Serum DHT was not quantifiable due to interference from metabolites of 11β-MNTDC preventing the precise separation of DHT from other compounds (16). Serum E2 concentrations were measured by liquid chromatography–tandem mass spectrometry (20) and serum LH was measured with a sensitive fluoroimmunometric assay previously described (21). Serum FSH and SHBG were measured by electrochemiluminescence immunoassay (Roche Diagnostics, Indianapolis, IN) validated against previously reported fluoroimmunometric assays. Free T was calculated using a common, validated equation (22).

Statistical analyses

The primary end points for the clinical study were the safety and tolerability of 11β-MNTDC as assessed by adverse events, vital signs, and safety laboratory tests. The secondary end points included the pharmacokinetics (PK) of serum 11β-MNTDC and 11β-MNT in fasting and fed states and pharmacodynamics (PD) of suppression of LH, FSH, T, and E2.

The number of participants on active treatment (n = 10) for this phase 1 clinical study was powered to provide at least a 80% statistical power to reject at least 30% of participants developing grade 3 adverse events using a one-sided exact test with target significance level of 0.05 for each administered dose.

The PK parameters for each sampling day for 11β-MNTDC were determined by noncompartmental methods and primarily assessed using the area under the curve (AUC) from 0 to 24 hours of serum 11β-MNTDC/11β-MNT levels generated by the 10 blood sampling times over 24 hours for each dose of 11β-MNTDC and computed using the trapezoid method. Other PK parameters assessed over 24 hours included Cavg (average concentration), Cmax (maximum concentration), Cmin (minimum concentration), and Tmax (time to reach Cmax). The elimination half-life, T1/2, was calculated assuming exponential decay when there were at least three measurable concentrations after Cmax.

Based on prior studies with oral administration of androgen esters, we anticipated a marked food effect on the PK (23). Therefore, we planned separate analyses under the fed and fasting conditions a priori. Mixed models incorporating repeated measurements were used to examine the effect of dose (0, 100, 200, 400, and 800 mg) on AUC, Cavg, Cmax, Cmin, and Tmax for serum 11β-MNTDC and 11β-MNT in the fasting and fed state. The ratios of 11β-MNT to 11β-MNTDC (representing the conversion of 11β-MNTDC to 11β-MNT in vivo) were calculated only in the fed state as serum concentrations of both compounds were below the lower limit of quantification in many samples after dosing when fasted. In an effort to maintain a type I error rate of 0.05, the Tukey-Kramer and the stepwise Bonferroni adjustments were used for all follow-up pairwise comparisons and multiple tests of safety measurements, respectively. The effect of 11β-MNTDC oral administration with food on serum T, free T, E2, LH, and FSH was analyzed by mixed model analogously for Cavg and Cmin. All analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC). Data are presented as mean ± SEM.

Results

In vitro receptor binding and agonist transactivation activity

The receptor binding activity of 11β-MNT, measured by the half-maximal inhibitory concentration (IC50), was greater than 10-fold that of DHT for AR and similar to progesterone for PR. The prodrug 11β-MNTDC had minimal affinity for AR and PR (Fig. 1A). The binding activity of both compounds to ERα and the GR was negligible (data not shown). In a cell-based receptor transactivation assay, the lowest dose of 11β-MNT tested (10−10 M) reached maximum agonist response; increasing the dose of 11β-MNT did not further increase the activity. The EC50 of 11β-MNT, calculated using nonlinear regression analysis extrapolated from the maximum to zero response (25.03 × 10−13 M), showed 30-fold higher androgenic activity than DHT (67.44 × 10−11 M) but lower progestational activity compared with progesterone (Fig. 1B). 11β-MNTDC was less androgenic and progestational than DHT and progesterone, respectively, and less androgenic and progestational than 11β-MNT (Fig. 1A). Both compounds had minimal transactivation activity for ERα and GR (data not shown).

Figure 1.

Figure 1.

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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.

Study participant demographics and safety

Of the 16 male participants screened, 12 enrolled and all completed the study. Four participants were excluded due to abnormal safety laboratory tests at screening. The characteristics of the participants are provided in Table 1.

Table 1.

Demographics (n = 12)

Characteristic Value
Age, y 39.1 ± 3.9 (21–49)
Ethnicity
 Not Hispanic or Latino 10 (83)
 Hispanic or Latino 2 (17)
Race
 Black or African American 5 (42)
 White 7 (58)
Weight, kg 85.7 ± 3.0 (74–98.6)
BMI, kg/m2 27.5 ± 1.1 (22.9–32.7)
Baseline T, ng/dL 515.3 ± 54.2 (310–737)
Baseline FSH, mIU/mL 3.9 ± 0.7 (1.38–9.70)
Baseline LH, mIU/mL 3.2 ± 0.4 (1.25–5.63)
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Values are presented as mean ± SEM (range) or number (%).

Abbreviation: BMI, body mass index.

Safety and tolerability

All doses were well tolerated, and there were no serious adverse events. All adverse events are summarized in an online repository (16). Two participants experienced transiently elevated serum aspartate aminotransferase, alanine aminotransferase, and creatinine kinase concentrations a few days after strenuous exercise. In one participant, this elevation in transaminases and creatinine kinase occurred prior to drug dosing. In the other subject, the elevation occurred 17 days after the 200-mg fasting dose. Both had resolution of their laboratory abnormalities without intervention and continued the study. Five subjects experienced weight gain of >4 kg, and mean weight increase was 2.97 ± 0.79 kg (P < 0.01) during the study. By the last dose of this sequential study, the 800-mg fed dose, there was a mean decrease in hematocrit by 3.2% ± 1.0% compared with baseline (P < 0.05). This decrease was due to phlebotomy. By the 800-mg fed dose, the subjects had undergone seven 24-hour pharmacokinetic inpatient visits; the total estimated blood loss over the course of the 12- to 20-week study was 800 to 1200 mL. Overall, there were no clinically significant changes in blood pressure, heart rate, ECG (including QTc interval), blood chemistry, lipid panel, or liver function.

PK and PD of 11β-MNTDC in the fasting state

When administered fasting, 11β-MNTDC was poorly absorbed, and only minimal concentrations of 11β-MNT were measurable regardless of the dose given. Therefore, PD effects were not evaluated (Fig. 2, Table 2).

Figure 2.

Figure 2.

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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.

Table 2.

PK of 11β-MNT and 11β-MNTDC After Single Oral Administration Fasting or After Food

Characteristic Placebo
100 mg
200 mg
400 mg
800 mg
Fasting Fed Fasting Fed Fasting Fed Fasting Fed Fasting Fed
11β-MNT
 11β-MNT AUC, ng/mL⋅24 h 12.0 ± 0.0 12.0 ± 0.0 12.0 ± 0.0 100.5 ± 9.6 16.4 ± 2.9 189.3 ± 30.9a 15.4 ± 3.4 339.6 ± 47.3a 77.1 ± 51.1 482.4 ± 57.9
 11β-MNT Cavg, ng/mL 0.5 ± 0.0 0.5 ± 0.0 0.5 ± 0.0 4.2 ± 0.4 0.7 ± 0.1 8.0 ± 1.3a 0.6 ± 0.1 14.1 ± 2.0a 3.2 ± 2.1 20.1 ± 2.4
 11β-MNT Cmax, ng/mL 0.5 ± 0.0 0.5 ± 0.0 0.5 ± 0.0 9.9 ± 1.1 1.6 ± 0.7 16.7 ± 2.5b 0.9 ± 0.4 31.8 ± 4.6a 5.5 ± 3.6 37.7 ± 4.1
 11β-MNT Tmax, h 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 7.1 ± 0.3 2.7 ± 1.6 6.9 ± 0.5 1.2 ± 1.2 6.6 ± 0.5 3.6 ± 1.5 10.7 ± 1.2b
11β-MNTDC
 11β-MNTDC AUC, ng/mL⋅24 h 48 ± 0 48 ± 0 136 ± 62 12816 ± 1500 567 ± 252 24,443 ± 4654a 920 ± 782 58,063 ± 8952b 8664 ± 5781 97,885 ± 14,004b
 11β-MNTDC Cavg, ng/mL 2 ± 0 2 ± 0 6 ± 3 534 ± 62 24 ± 11 1018 ± 194a 38 ± 33 2419 ± 373b 361 ± 241 4079 ± 584b
 11β-MNTDC Cmax, ng/mL 2 ± 0 2 ± 0 18 ± 10 2986 ± 534 134 ± 76 5684 ± 963 149 ± 127 13,541 ± 2742b 1823 ± 1165 18,554 ± 2954
 11β-MNTDC Tmax, h 0.0 ± 0.0 0.0 ± 0.0 4.9 ± 1.0 4.7 ± 0.3 6.0 ± 0.9 4.7 ± 0.3 5.8 ± 1.3 5.0 ± 0.6 5.6 ± 1.0 5.6 ± 0.4
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Values are mean ± SEM. Lower limit of quantification: 11β-MNT = 0.5 ng/mL; 11β-MNTDC = 2.0 ng/mL. P values were assessed for fed groups only. Compared with placebo, all dose levels P < 0.001.

a

Comparison between doses (e.g., 200 mg compared with 100 mg, 400 mg compared with 200 mg, 800 mg compared with 400 mg): P < 0.01.

b

Comparison between doses (e.g., 200 mg compared with 100 mg, 400 mg compared with 200 mg, 800 mg compared with 400 mg): P < 0.05.

Effect of food on PK of 11β-MNTDC and 11β-MNT

Concomitant administration of a high-fat meal (50% of total calories as fat) with 11β-MNTDC markedly increased its absorption, resulting in significantly higher AUC, Cavg, and Cmax of serum 11β-MNTDC and 11β-MNT concentrations compared with fasting doses and placebo (Table 2 and Fig. 2, P < 0.0001 for all dose concentrations). In the fed state, there was a significant dose-related effect as 11β-MNTDC and 11β-MNT demonstrated higher AUC, Cavg, and Cmax at the 400-mg and 800-mg doses compared with the 200-mg dose (adjusted P < 0.05 for all comparisons) (Table 2).

There was one participant whose serum 11β-MNTDC and 11β-MNT concentrations were less than one-tenth that of the other nine men after taking the 200-mg and 800-mg doses with food (he was randomized to placebo at the 400-mg dose). His PK data were considered an outlier and not included in the PK analyses. This participant may have a limited ability to absorb 11β-MNTDC or markedly increased clearance.

The Tmax for 11β-MNTDC at all doses was between 4 and 8 hours. For 11β-MNT, the Tmax for the 100-, 200-, and 400-mg doses was between 4 and 8 hours and, for 800 mg, 8 to 12 hours. Both 11β-MNTDC and 11β-MNT serum concentrations decreased but remained detectable 24 hours after the 800-mg fed dose. At 48, 72, and 96 hours after the 800-mg fed dose, seven, two, and one of nine participants had detectable 11β-MNTDC concentrations and six, one, and zero of nine participants had detectable 11β-MNT, respectively. The conversion of 11β-MNTDC to 11β-MNT at Cmax was very low at all dosages: 100 mg, 0.42% ± 0.09%; 200 mg, 0.37% ± 0.07%; 400 mg, 0.29% ± 0.04%; and 800 mg, 0.23% ± 0.3%. The elimination half-lives for 11β-MNTDC and 11β-MNT were similar across all doses in the fed state, averaging 2.5 ± 0.1 hours for 11β-MNTDC and 6.1 ± 0.3 hours for 11β-MNT.

PD effects of 11β-MNTDC when administered with food

After a single dose of oral 11β-MNTDC administered with a high-fat meal, compared with placebo and baseline levels, statistically significant suppression was observed for serum LH Cavg at 200 mg (adjusted P = 0.007) (Fig. 3); total T Cavg at 200, 400, and 800 mg (adjusted P = 0.046, 0.0009, and 0.009, respectively); and total T Cmin at 200, 400, and 800 mg (adjusted P = 0.01, 0.002, and 0.002, respectively) (Fig. 3). Serum calculated free T concentrations followed the same trend as total T, with statistically significant suppression at 400 and 800 mg (adjusted P = 0.007 and 0.03). No statistically significant suppression of FSH (Fig. 3), E2 (Fig. 3), or SHBG (data not shown) was seen at any dose over the 24-hour postdosing period.

Figure 3.

Figure 3.

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Serum concentrations, Cavg (over 24 hours), and Cmin 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.

Discussion

We present data supporting the continued development of 11β-MNTDC as a potential once-daily oral male hormonal contraceptive. We demonstrate that 11β-MNTDC has minimal affinity for AR and PR, but when converted into its active form, 11β-MNT, the receptor binding affinity for AR was higher than the potent androgen DHT. Similarly, 11β-MNT bound as avidly to PR as progesterone. Oral 11β-MNTDC was well tolerated by healthy men at single doses up to 800 mg, without liver toxicity or serious side effects. Even with single doses, oral 11β-MNTDC suppressed serum T concentrations when administered with food. There was no suppression of FSH, and statistically significant suppression of LH was seen only in the 200-mg group. As the sample size was small, and there was no dose-response relationship observed, a single dose of 11β-MNTDC might not be sufficient to suppress gonadotropins. Repeat dose studies are under way to confirm that oral 11β-MNTDC suppresses LH, FSH, and T production. T was suppressed following 11β-MNTDC administration at the 200-, 400-, and 800-mg fed doses despite the lack of consistent suppression of gonadotropins; 11β-MNT may have direct effects on the testes via progesterone receptors (24).

The combination of a progestin with an androgen enhances the suppression of spermatogenesis (12). Oral levonorgestrel, a potent progestin, when combined with T administered transdermally, subcutaneously, intramuscularly, or as an implant, induces greater suppression of spermatogenesis than T alone (25–27). However, these regimens require the administration of T via injection, implant, or patch with a daily oral progestin; using two different delivery methods simultaneously is unlikely to be practical as a contraceptive method. Our goal is to develop a single-agent male contraceptive that can be administered orally. Multinational surveys indicate that many men prefer daily pills over other modes of administration (13, 14). Oral androgen administration has been challenging. 17-α-Alkylated androgens such as methyltestosterone can cause liver toxicity (28). Oral TU is safe (29) but it is not yet approved for use in the United States. Moreover, TU requires at least twice-daily dosing and was not effective in suppressing spermatogenesis in a pilot study (15).

In contrast to T, DMA and 11β-MNT (derivatives of 19-nortestosterone) have both potent androgenic and progestational activity (30). Neither compound is 17α-alkylated, and both have been shown to lack hepatotoxicity in preclinical studies. Prior studies showed that 11β-MNT does not require 5α-reduction to exert maximal androgenic effects and does not undergo significant 5α-reduction in vivo in rats (31). In rodent studies, 11β-MNT has similar stimulating effects on the prostate and seminal vesicles compared with T but significantly higher stimulating effects on the levator ani muscle (17); there might be a dosage of 11β-MNT that provides normal androgenic effects on muscle and other androgen-dependent tissues except with relatively less effect on the prostate. Future studies should examine the relative effects of 11β-MNT on human prostatic and nonprostatic tissues. Although 11β-MNT is not aromatized to estrogens (32), it is reassuring that preclinical studies demonstrating subcutaneous administration of 11β-MNTDC to castrated rats maintained bone mineral density comparable to T enanthate (17). Because estradiol plays an important role in maintaining bone and sexual health as well as limiting adiposity in men (33, 34), these clinical end points will need to be carefully followed in future longer-term, repeat-dose studies of 11β-MNTDC.

Oral 11β-MNTDC was well tolerated in healthy men at single doses up to 800 mg. There were no serious adverse events. Two participants had simultaneous elevation of serum liver enzymes and creatinine kinase attributed to strenuous exercise with concomitant increase in serum creatinine kinase. A few participants noted acne and mild changes in libido (both increased and decreased) that might be expected with androgen administration. These side effects are similar to those noted in other androgen-progestin combination studies (26, 27, 35). The potential impact of multiple doses of oral 11β-MNTDC on sexual function and desire will be evaluated prospectively in future, repeat-dose, placebo-controlled studies.

Prior studies have suggested that oral androgenic progestins may contribute to weight gain compared with androgens alone (26, 35). Weight gain of over 4 kg was noted in five of 12 participants. The effect of each individual dose of the drug on weight was not statistically significant, but cumulatively, the mean weight of participants increased throughout the study with increasing doses of 11β-MNTDC. The design of the study makes it difficult to ascertain whether the observed weight gain is dose related, coincidental, or attributable to the high-fat breakfasts consumed with each dose. The relative contribution of lean and fat mass to any observed weight gain associated with longer-term dosing of 11β-MNTDC will be the subject of future investigations.

Similar to other androgens with longer fatty acid side chains such as TU (23, 36) and DMAU (37, 38), absorption of 11β-MNTDC is dependent on administration with food. Lipophilic medications have increased bioavailability when administered with a high-fat meal because of increased drug solubility, stimulation of bile secretion (39), or both. Further studies will be required to elucidate the amount of fat required to optimize absorption of oral 11β-MNTDC. One participant had serum 11β-MNTDC and 11β-MNT concentrations that were less than one-tenth that of the other nine men after taking the 200-mg and 800-mg doses with food (he was randomized to placebo at the 400-mg dose). His PK data were considered an outlier and not included in the PK analyses. This participant may have a limited ability to absorb 11β-MNTDC or markedly increased clearance. There was no clinical difference between this participant and the other 11 participants; his body mass index and weight were not outliers, and he did not have any nausea, vomiting, or diarrhea during the study.

The conversion of 11β-MNTDC to 11β-MNT appears to be very low (0.29% to 0.42%). This conversion rate is approximately one-tenth the conversion of DMAU to DMA (38) and about one-fiftieth the conversion of TU to T in men (36, 40). The low conversion of the prodrug 11β-MNTDC to the active compound 11β-MNT should be taken into consideration in the development of the oral formulation of this agent. Given the requirement for concomitant food administration for oral absorption, the large variability in the absorption of 11β-MNTDC between participants (including one very poor absorber), and the low conversion of the prodrug to the active compound, an intramuscular or subcutaneous injection or an implant may be more effective in delivering 11β-MNT and require less of the prodrug 11β-MNTDC. Importantly, both 11β-MNTDC and 11β-MNT serum concentrations decreased after cessation of administration, but most men in the 800-mg group had measurable concentrations 48 hours following dosing, suggesting it may be possible to administer 11β-MNTDC at intervals of 24 hours or more. Repeated dosing studies are in progress to examine drug accumulation and will facilitate determination of the optimal dosing frequency and quantity. Further clinical studies are necessary to determine the relative effectiveness of oral DMAU and 11β-MNTDC for suppression of spermatogenesis for male contraception or hormonal therapy in men.

In conclusion, our receptor binding and transactivation assays suggest that de-esterification of the 11β-MNTDC into its active form is essential for maximal biological activity in men. We demonstrate that a single, oral dose of 11β-MNTDC up to 800 mg is safe and that 11β-MNTDC requires concomitant food administration for optimal absorption and effectiveness. Oral 11β-MNTDC is promising as a potential single-agent male contraceptive, and repeated dosing studies to ensure safety, tolerability, and suppression of spermatogenesis are warranted for this novel androgen with progestational activity.

Acknowledgments

We thank our research coordinators Xiao-Dan Han, Elizabeth Ruiz, Lauryn Raj, and Kathryn Torrez-Duncan for their assistance with the study. We thank the staff of the Endocrine and Metabolic Research Laboratory at LA BioMed and the University of Washington Center for Research in Reproduction and Contraception and, most important, our research participants.

Financial Support: The Los Angeles Biomedical Research Institute (LA BioMed) center was supported by the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD) Contraceptive Clinical Trial Network Contract HHSN27520130024I (to R.S.S.), Task Orders HHSN 27500001 and 27500006, and the National Center for Advancing Translational Sciences of the National Institutes of Health award to the UCLA Clinical and Translational Science Institute (UL1TR000124) at Harbor-UCLA/LA BioMed. The University of Washington center was supported by NICHD Contraceptive Clinical Trial Network Contract HHSN275201300025I (to W.J.B.), Task Orders HHSN27500005, the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000423, and the National Institute of Diabetes and Digestive and Kidney Diseases training grant 5T32 DK007247-39-40 (to S.W.). S.T.P. is also supported by the Robert McMillen Professorship in Lipid Research. P.Y.L. was supported in part by K24 HL138632.

Clinical Trial Information: ClinicalTrials.gov no. NCT02754687 (registered 28 April 2016).

This work was presented in part at the 100th Annual Meeting of the Endocrine Society, ENDO 2018, March 17–20, 2018, Chicago, IL.

Disclosure Summary: S.T.P. and J.K.A. have served as consultants for Clarus Therapeutics. R.S.S. is a consultant for Clarus Therapeutics and receives research support from Clarus Therapeutics and Testosterone Replacement Therapy Manufacturers Consortium. C.W. receives research support from Clarus Therapeutics, Antares, TesoRX, and Testosterone Replacement Therapy Manufacturers Consortium. T.P. and K.K. are employees of SRI International and M.S.L. and D.L.B. are employees of the US government. The remaining authors have nothing to disclose.

Glossary

Abbreviations:

11β-MNT

11β-methyl-19-nortestosterone

11β-MNTDC

11β-methyl-19-nortestosterone-17β-dodecylcarbonate

AR

androgen receptor

AUC

area under the curve

Cavg

average concentration

Cmax

maximum concentration

Cmin

minimum concentration

DMA

dimethandrolone

DMAU

dimethandrolone undecanoate

E2

estradiol

ER

estrogen receptor

GR

glucocorticoid receptor

GST

glutathione S-transferase

PD

pharmacodynamics

PK

pharmacokinetics

PR

progesterone receptor

SHBG

sex hormone binding globulin

T

testosterone

Tmax

time to reach maximum concentration

TU

testosterone undecanoate

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