TESTOSTERONE CONTAINING PHARMACEUTICAL COMPOSITION

Abstract

We disclose a pharmaceutical composition adapted for oral delivery comprising native testosterone; a treatment regimen comprising administration of the composition(s); and methods and uses for the treatment of hormone related conditions such as hypogonadism in human male, female and transgender subjects.

Claims

1. A pharmaceutical composition adapted for oral administration comprising at least 10% w/w native testosterone, at least 36% w/w sesame oil, at least 28% w/w propylene glycol monolaurate, at least 9% w/w ethanol and at least 14% w/w benzyl alcohol.

2. The pharmaceutical composition according to claim 1 wherein the composition comprises or consists essentially of: (a) about 10% w/w native testosterone; at least 36% w/w sesame oil; at least 28% w/w propylene glycol monolaurate; at least 9% w/w ethanol; and at least 16% w/w benzyl alcohol, or (b) about 10% w/w native testosterone; at least 36% w/w sesame oil; at least 28% w/w propylene glycol monolaurate; at least 11% w/w ethanol; and at least 14% w/w benzyl alcohol.

3. (canceled)

4. A method for treating a hormone related condition in a human subject comprising administering a pharmaceutical composition comprising: native testosterone, sesame oil, propylene glycol monolaurate, ethanol and benzyl alcohol wherein the composition is administered orally at least once in a 24-hour period to the human subject, thereby treating the hormone related condition in the human subject.

5.-8. (canceled)

9. The method of claim 4 wherein the pharmaceutical composition comprises; between 2% to 11% w/w testosterone, 9% to 11% w/w native testosterone, About 10% w/w native testosterone, at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% or 41% w/w sesame oil, at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or 31% w/w propylene glycol monolaurate, at least 5, 6, 7, 8, 9, 10 or 11% w/w ethanol, and at least 13, 14, 15, 16, 17, 18 19 or 20% benzyl alcohol.

10.-12. (canceled)

13. The method according to claim 4, wherein the pharmaceutical composition comprises: (a) 2 to 10% w/w native testosterone; at least 40% w/w sesame oil; at least 30% w/w propylene glycol monolaurate; at least 5% w/w ethanol; and at least 15% w/w benzyl alcohol, (b) 9-11% w/w native testosterone; at least 35% w/w sesame oil; at least 27% w/w propylene glycol monolaurate; at least 8% w/w ethanol; and at least 13% w/w benzyl alcohol, (c) about 10% w/w native testosterone: at least 36% w/w sesame oil; at least 28% w/w propylene glycol monolaurate; at least 9% w/w ethanol; and at least 16% w/w benzyl alcohol, or (d) about 10% w/w native testosterone; at least 36% w/w sesame oil; at least 28% w/w propylene glycol monolaurate; at least 11% w/w ethanol; and at least 14% w/w benzyl alcohol.

14.-16. (canceled)

17. The method according to claim 4, wherein the human subject is administered the pharmaceutical composition one, two, three or four times in a 24-hour period and wherein the administrations are temporally separated during the 24-hour period.

18. (canceled)

19. The method according to claim 4, wherein: (a) the total native testosterone dose is administered between 00:00 hours and 12:00 hours and one third of the total native testosterone dose is administered between 12:00 and 24:00 hours; (b) wherein 50% to 90% of the total native testosterone dose is administered between 00:00 to 12:00 hours and 50% to 10% of the total native testosterone dose is administered between 12:00 to 24:00 hours; (c) wherein 55% to 70% of the total native testosterone dose is administered between 00:00 to 12:00 hours and 45% to 30% of the total native testosterone dose is administered between 12:00 to 24:00 hours; or (d) wherein 50% of the total native testosterone dose is administered between 00:00 to 12:00 hours and 50% of the total native testosterone dose is administered between 12:00 to 24:00 hours.

20.-22. (canceled)

23. The method according to claim 4 wherein the hormone related condition is delayed puberty, hypogonadism, primary hypogonadism, secondary hypogonadism, Constitutional Delay of Growth and Puberty, familial Constitutional Delay of Growth and Puberty, idiopathic Constitutional Delay of Growth and Puberty, cardiovascular disease, a disease associated with cardiovascular disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, metabolic syndrome, type II diabetes, gender reassignment, reduced sexual libido, or erectile dysfunction.

24.-38. (canceled)

39. The method according to claim 4 wherein the human subject is in a fasted or fed state before administration of the pharmaceutical composition.

40. (canceled)

41. A method for treating a hormone related condition in a human subject who would benefit from administration of native testosterone comprising administering at least a first and a second pharmaceutical compositions wherein, the first composition comprises between 2.5-7.5% w/w native testosterone, sesame oil, propylene glycol monolaurate, ethanol and benzyl alcohol; and the second composition comprises at least 9% w/w native testosterone, sesame oil, propylene glycol monolaurate, ethanol and benzyl alcohol; wherein the first and second compositions are administered orally at least once in a 24-hour period to the human subject to normalise serum testosterone.

42. The method according to claim 41 (a) wherein the first composition comprises: 2.5 to 7.5% w/w native testosterone; at least 40% w/w sesame oil; at least 30% w/w propylene glycol monolaurate; at least 5% w/w ethanol; and at least 15% w/w benzyl alcohol, (b) wherein the second composition comprises or consists essentially of: 9-11% w/w native testosterone; at least 35% w/w sesame oil; at least 27% w/w propylene glycol monolaurate; at least 8% w/w ethanol; and at least 13% w/w benzyl alcohol, (c) wherein the second compositions comprises or consists essentially of: about 10% w/w native testosterone; at least 36% w/w sesame oil; at least 28% w/w propylene glycol monolaurate; at least 9% w/w ethanol; and at least 16% w/w benzyl alcohol, or (d) wherein the second composition comprises or consists essentially of: about 10% w/w native testosterone; at least 36% w/w sesame oil; at least 28% w/w propylene glycol monolaurate; at least 11% w/w ethanol; and at least 14% w/w benzyl alcohol.

43.-45. (canceled)

46. The method according to claim 41 wherein the human subject is administered the first and second composition simultaneously or temporally separated during the 24-hour period.

47. The method according to claim 41 wherein the hormone related condition is delayed puberty, hypogonadism, primary hypogonadism, secondary hypogonadism, failure of puberty due to either primary or secondary hypogonadism, Constitutional Delay of Growth and Puberty, familial Constitutional Delay of Growth and Puberty, idiopathic Constitutional Delay of Growth and Puberty, cardiovascular disease, a disease associated with cardiovascular disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, metabolic syndrome, type II diabetes, gender reassignment, reduced sexual libido, or erectile dysfunction.

48.-62. (canceled)

63. The method according to claim 41 wherein the human subject is in a fasted or fed state before administration of the pharmaceutical composition.

64. (canceled)

65. A method for treating a hormone related condition in a human female subject who would benefit from administration of native testosterone comprising administering to the human female subject a pharmaceutical composition comprising: native testosterone, sesame oil, propylene glycol monolaurate, ethanol and benzyl alcohol wherein the composition is administered orally at least once in a 24 hour period to the human female subject to normalise serum testosterone.

66. A method for treating frailty in a human subject comprising administering to the human subject a pharmaceutical composition comprising: native testosterone, sesame oil, propylene glycol monolaurate, ethanol and benzyl alcohol wherein the composition is administered orally to the human subject to increase serum testosterone.

67. A method for treating Turner's syndrome in a human female subject comprising administering to the human female subject a pharmaceutical composition comprising: native testosterone, sesame oil, propylene glycol monolaurate, ethanol and benzyl alcohol wherein the composition is administered orally to the human female subject to increase serum testosterone.

68. A process to produce a composition comprising native testosterone comprising i) forming a homogeneous preparation comprising sesame oil, propylene glycol monolaurate, benzyl alcohol and ethanol; ii) adding native testosterone at a concentration of about 13% w/w to said homogeneous preparation to form a combined testosterone preparation; and iii) mixing the combined preparation to dissolve testosterone to form a substantially clear preparation.

69.-72. (canceled)

Description

[0485] An embodiment of the invention will now be described by example only and with reference to the following Figures and tables:

[0486] FIG. 1: Serum Total Testosterone following single dose of either Testosterone Undecanoate 80 mg or DITEST 120 mg fed or DITEST 200 mg fasted or fed;

[0487] FIG. 2: Serum DHT following single dose of either Testosterone Undecanoate 80 mg or DITEST 120 mg fed or DITEST 200 mg fasted or fed.

MATERIALS AND METHODS

[0488] DITEST contains testosterone as the sole active ingredient. The chemical description of the active ingredient is provided below: [0489] Chemical Name (International Union of Pure and Applied Chemistry [IUPAC]) (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopent a[a]phenanthren-3-one [0490] Other names Androst-4-en-3-one, 17-hydroxy-, (17β)-b, 17β-Hydroxyandrost-4-en-3-one [0491] Chemical Abstracts Service 58-22-0 [0492] (CAS) Registry No.

##STR00001##

TABLE-US-00001 General Properties Molecular Formula C.sub.19H.sub.28O.sub.2 Molecular Weight 288.41 g/mol Description (drug substance) White crystalline powder Melting Point 152-156° C. Aqueous Solubility <1 mg/mL (insoluble) at 20° C. in water Non-aqueous Solubility (wt/vol) at 20° C. in: Alcohol 1 in 5 parts Dehydrated alcohol 1 in 6 parts Chloroform 1 in 2 parts Ether 1 in 100 parts Ethyl oleate slightly soluble Dioxane soluble Vegetable oils soluble
Testosterone is a Schedule 4 Part II controlled drug (androgenic and anabolic steroids) in the UK. It belongs to the pharmacotherapeutic group of androgens (ATC code G03B A03).

TABLE-US-00002 TABLE 1 DITEST FORMULATION Quantity Quantity per Ingredient % w/w capsule (mg) Function Testosterone 5.43 40.0 Active ingredient Sesame Oil 41.39 305.0 Carrier Propylene Glycol 31.62 233.0 Surfactant Monolaurate Benzyl Alcohol 16.29 120.0 Solvent Ethanol 5.27 38.83 Solvent Gelatin — — Capsule shell

TABLE-US-00003 TABLE 2 Testosterone 100 mg/g Formulation 2 (CIIIN) Testosterone 100 mg/g Formulation 1 (DEA Reg.# RR0240919 (CIIIN) (DEA Reg.# RR0240919 OET-00791183 OET-00791182 Lot 20MX-10 Lot 20MX-09 120 mg 120 mg (12.5% EtOH) (10% EtOH/18% Benzyl Alcohol) Active Active Raw Materials Placebo W/W % mg/cap W/W % Placebo W/W % mg/cap W/W % Testosterone CHIN, 120.00 10.00% 120.00 10.00% EP Dehydrated Alcohol, 12.5% 135.00 11.25% 10.0% 108.00 9.00% USP, EP Benzyl Alcohol, NF, 15.6% 168.68 14.06% 18.0% 194.40 16.20% EP Propylene Glycol 31.2% 336.61 28.05% 31.2% 336.77 28.06% Monolaurate, NF, EP (Type II)—Lauroglycol 90 Sesame Oil, NF— 40.7% 439.71 36.64% 40.8% 440.83 36.74% Super Refined Sesame NF NP-LQ- (MH) Total of All 100.0% 1200.000 100.00% 100.0% 1200.000 100.00% Ingredients

TABLE-US-00004 TABLE 3 Serum Total Testosterone following single dose of either Testosterone Undecanoate 80 mg or (A) DITEST 120 mg fed or (B) DITEST 200 mg fed; Summary of Statistical Analysis of Baseline-Adjusted Serum Testosterone C.sub.max and AUC.sub.(0-10) Pharmacokinetic Data - Study Drug Comparison PK Set A Geometric LSMeans Geometric Cohort 1: LSMean Ratio Cohort 1: 80 mg (90% C.I.) 120 mg Testosterone 120 mg DITEST - Undecanoate - DITEST/80 mg Number in Fed Fed Testosterone Parameter Comparison (N = 12) (N = 12) Undecanoate C.sub.max 12 14.5 26.2 55.58 (nmol/L) (44.99-68.65) AUC.sub.(0-10) 12 41.9 81.8 51.26 (h*nmol/L) (34.70-75.71) Source Listing: 16.2.5.5 and 16.2.5.9; Produced 17 Dec. 2019 13:11 Page 1 of 2 Result obtained using ANOVA according to a two-way cross over model with fixed effects for treatment, study period, treatment sequence and subject nested within sequence. B Geometric LSMeans Geometric Cohort 1: LSMean Ratio Cohort 2: 80 mg (90% C.I.) 200 mg Testosterone 200 mg DITEST/ Undecanoate - DITEST/80 mg Number in Fed Fed Testosterone Parameter Comparison (N = 11) (N = 12) Undecanoate C.sub.max 23 23.0 26.2 88.01 (nmol/L) (58.22-133.05) AUC.sub.(0-10) 23 71.6 81.8 87.54 (h*nmol/L) (54.64-140.24) Source Listing: 16.2.5.5 and 16.2.5.9; Produced 17 Dec. 2019 13:11 Page 2 of 2 Result obtained using ANOVA with a fixed effect of treatment (t-test for two independent groups).

TABLE-US-00005 TABLE 4 Serum Total Testosterone following single dose of either DITEST 200 mg fasted or fed; Summary of Statistical Analysis of Baseline-Adjusted Serum Testosterone - Food Effect PK Set Cohort 2 Geometric LSMeans 200 mg 200 mg Geometric DITEST - DITEST - LSMean Ratio Number in Fed Fasted (90% C.I.) Parameter Comparison (N = 11) (N = 11) Fed/Fasted C.sub.max 11 22.9 26.9 85.14 (nmol/L) (57.54-125.97) AUC.sub.(0-10) 11 70.5 74.9 94.20 (h*nmol/L) (66.14-134.17) Source listing: 16.2.5.5 and 16.2.5.10; Produced: 17 Dec. 2019 13:12 Page 1 of 1 Results obtained using an ANOVA according to a two-way cross over model with fixed effects for treatment, study period, treatment sequence and subject nested within sequence.

TABLE-US-00006 TABLE 5 Serum Total Testosterone following single dose of either DITEST 120 mg fed or DITEST 200 mg fed DITEST-001 Table 14.4.2.7 Summary of Statistical Analysis of Baseline-Adjusted Serum Testosterone C.sub.max and AUC.sub.(0-10) Pharmacokinetic Data - Dose Level Comparison PK Set Geometric LSMeans Cohort 1: Cohort 2: Geometric 120 mg 200 mg LSMean Ratio DITEST - DITEST - (90% C.I.) Number in Fed Fed 120 mg DITEST/ Parameter Comparison (N = 11) (N = 11) 200 mg DITEST C.sub.max 23 14.5 23.0 63.15 (nmol/L) (39.21-101.70) AUC.sub.(0-10) 23 41.9 71.6 58.55 (h*nmol/L) (32.53-105.39) Source Listing: 16.2.5.5 and 16.2.5.11; Produced 17 Dec. 2019 13:12 Page 1 of 1 Result obtained using ANOVA with a fixed effect of treatment (t-test for two independent groups).

Formulation

[0493] DITEST is an oral, immediate-release, gelatin capsule containing 40 mg native testosterone and the following excipients: sesame oil, ethanol, benzyl alcohol and propylene glycol monolaurate. The capsule shell also contains and glycerine. Fractionated coconut oil, isopropyl alcohol, lecithin and Phosal 53 MCT (lecithin in caprylic/capric triglycerides, alcohol, glyceryl stearate, oleic acid and ascorbyl palmitate) are used as processing aids during encapsulation and may be present in trace amounts. DITEST is presented as a liquid-fill in anopaque, soft gelatin capsules. Testosterone drug substance is USP/EP grade and is manufactured in accordance with Good Manufacturing Practice (GMP). All excipients are European Pharmacopoeia grade and approved for use in human adults at the quantities to be administered within the clinical development programme. The gelatin used to form the capsule shell is certified (European Directorate for the Quality of Medicines & Healthcare [EDQM] Certificate of Suitability [CEP]) as bovine spongiform encephalopathy (BSE)/transmissible spongiform encephalopathy (TSE) free. DITEST is manufactured in accordance with GMP.

[0494] DITEST is packaged in, for example, aluminium-aluminium blister packs. Blisters are contained within cardboard cartons. DITEST is labelled in compliance with the requirements of Annex 13 (Manufacture of Investigational Medicinal Products) of EudraLex (The Rules Governing Medicinal Products in the European Union)—Volume 4: EU Guidelines to GMP.

Method of Preparation of Composition Comprising 10% wt Native Testosterone

[0495] 1. All excipients were weighed and added into an amber glass bottle in order of decreasing mass (sesame oil, propylene glycol, benzyl alcohol and ethanol) (This approach was adopted to reduce evaporation losses as Ethanol is volatile)

[0496] 2. The blend was mixed by hand until uniform

[0497] 3. Testosterone was added at a target weight of 2.667 g (133.3 mg/g target concentration) to the amber glass bottle and a stirrer bar added to the bottle.

[0498] 4. The formulation was mixed using magnetic stirrer (setting 5) initially mixed at for 48 minutes

[0499] 5. Continued mixing was completed on the formulation for a total of 4 days prior to solubility assessment. at ambient temperature.

[0500] Solubility assessment of the 10% w/w testosterone composition was performed as follows:

[0501] 1. The formulations were transferred into centrifuge tubes

[0502] 2. The formulations were centrifuged for 15-20 mins at 15,000 rpm

[0503] 3. The supernatant was analysed by analytical and the testosterone content determined

[0504] Soft gel Fill Challenge Method of Preparation of the composition comprising 10 wt % ethanol

[0505] 1. All excipients were weighed and added into an amber glass bottle in order of decreasing mass (Sesame oil, Propylene glycol, Benzyl Alcohol and ethanol) 2.

[0506] Testosterone was added to the amber glass bottle and a stirrer bar added to the bottle.

[0507] 3. The formulation was mixed using magnetic stirrer initially at 300 rpm and gradually increased to 500 rpm over a 3-hour 20 minute mixing period.

[0508] The placebo was manufactured as follows:

[0509] The excipients were combined in aa bottle and hand mixed for 1 minute.

Storage Conditions

[0510] DITEST should be stored in a dry place at 5° C. to 25° C., with the temperature controlled and monitored. Temperature monitoring devices will be included with shipments of DITEST to confirm the transportation conditions are acceptable.

[0511] There is an unmet need for a native oral testosterone therapy for men with androgen (testosterone) deficiency. Current therapy for most hypogonadal patients in Europe and the United States of America (USA) is with either intramuscular injections or gels. These therapies have the disadvantages of pain with injections, skin reactions, and potential spread to partners with gels. At the time this study was designed, there was only one oral formulation of testosterone undecanoate on the market in the UK, but at that time this was not approved in the USA. DITEST is a novel formulation of native testosterone. In a pre-clinical study DITEST showed good absorption after oral administration, so it was investigated further in this study for its safety and pharmacokinetics (PK) in adult men with hypogonadism. Testosterone undecanoate is considered mainly absorbed through intestinal lymphatics, along with dietary lipids, whilst DITEST was formulated to permit absorption without the requirement for dietary lipids. To examine the proportions absorbed through lymphatics, the aqueous and lipid fractions of serum were separated for the measurement of serum testosterone. Since this was a first-in-human study, participants were closely monitored as inpatients during dosing.

Methodology

[0512] The study was conducted in male participants from 18 to 80 years of age requiring testosterone replacement therapy for primary or secondary hypogonadism. The study was a randomized, active control, single dose, 2-way cross-over study in 2 cohorts. In each cohort participants who met the entry criteria at screening and baseline were randomized to one of 2 sequences:

[0513] Cohort 1: single dose of 120 mg (3×40 mg) DITEST followed by a single dose of 80 mg (2×40 mg) testosterone undecanoate or a single dose of 80 mg (2×40 mg) testosterone undecanoate followed by a single dose of 120 mg (3×40 mg) DITEST. The 2 treatments were separated by a minimum of a 7-day washout period, with both treatments given in the fed state.

[0514] Cohort 2: single dose of 200 mg (5×40 mg) DITEST (fed) followed by a single dose of 200 mg DITEST (fasted) or a single dose of 200 mg DITEST (fasted) followed by a single dose of 200 mg (5×40 mg) DITEST (fed). The 2 treatments were separated by a minimum of a 7-day washout period.

[0515] Twelve participants were to be recruited into each cohort (note: participants from Cohort 1 could be entered into Cohort 2 after a washout period of at least 3 months between cohorts). Participants were not recruited into Cohort 2 until the results of participants treated in Cohort 1 had been evaluated (this review determined if the intended dose for Cohort 2 needed to be adjusted). No other testosterone treatments were allowed for the duration of each cohort (including the washout periods) (note: participants who entered Cohort 1 were able to revert to their usual testosterone treatment, if applicable, on completion of this cohort and prior to screening for Cohort 2, if applicable). Each participant was required to attend the study site for a minimum of either 4 or 5 visits per cohort: a screening assessment, an evaluation of baseline testosterone levels after the washout period from the participant's current medication (only for participants currently on testosterone replacement therapy), both dosing days, and a follow-up visit at the end of the study. On each dosing day, participants were to remain in the study site and PK blood and saliva samples were taken at −0.5, −0.25 (Cohort 1 only), 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, and 10 hours. Further PK blood and saliva samples could be taken at up to 2 additional timepoints per period if deemed necessary based on emerging data. This was noted in the trial master file (TMF) and notified to the independent ethics committee (IEC). If necessary, for practical reasons, participants could stay overnight at the study site or at a nearby hotel the night before and/or the night after the dosing days. In Cohort 2, if participants failed to fast overnight, they could be asked to re-schedule a treatment visit.

Diagnosis and Main Criteria for Inclusion and Exclusion:

Main Inclusion Criteria:

[0516] Male participants aged 18 to 80 years. [0517] Diagnosis of primary testicular failure or secondary hypogonadism due to known pituitary disease or congenital deficit. [0518] Body mass index (BMI) >18 kg/m.sup.2 and <35 kg/m.sup.2. [0519] Testosterone level <8 nmol/L after washout of current testosterone treatment, if applicable. [0520] Normal prostate specific antigen (PSA) levels based on the age of the participant.

Main Exclusion Criteria:

[0521] Participants with a past history of or current prostate cancer, male breast cancer or hepatic neoplasm. [0522] Participants with a history of or current myocardial infarction (MI), unstable cardiovascular disease, or clinically relevant findings on the screening electrocardiogram (ECG) (as determined by the Investigator). [0523] Participants with other unstable or inadequately treated endocrine conditions. [0524] Haematocrit levels >0.5 at baseline.

Investigational Product, Dose, Mode of Administration, Batch Numbers:

[0525] DITEST as an immediate release soft gelatin capsule for oral administration. Each capsule contained 40 mg native testosterone in a lipid formulation.

[0526] Cohort 1 Low dose: 120 mg (3×40 mg capsules). Batch number 137001-03A

[0527] Cohort 2 High dose: 200 mg (5×40 mg capsules). Batch number 137001-F1.

Duration of Treatment

[0528] In each cohort, a participant received 2 single doses of study intervention separated by a washout period of at least 7 days.

Control Product, Dose, Mode of Administration, Batch Numbers:

[0529] Testosterone undecanoate 40 mg capsule for oral administration. Each capsule contained 40 mg testosterone undecanoate, equivalent to 25.3 mg testosterone. Cohort 1 dose: 80 mg (2×40 mg capsules). Batch numbers 193376 and 198015.

Endpoints:

Primary Endpoint

[0530] Testosterone serum concentrations after administration of a single dose of 120 mg or 200 mg DITEST and 80 mg testosterone undecanoate in the fed state, as measured by the primary PK parameters of maximum serum concentration (C.sub.max) and the area under the curve from 0 to 10 hours (AUC.sub.0-10).

Secondary Endpoints

[0531] Testosterone serum concentrations after administration of a single 200 mg dose of DITEST in the fed and fasted states, as measured by the primary PK parameters of C.sub.max and AUC.sub.0-10. [0532] AEs observed throughout the study. [0533] Changes during the study in vital signs, ECG and safety laboratory data.

[0534] Exploratory Endpoints: [0535] To assess the levels of testosterone and DHT in serum. [0536] To assess the levels of testosterone and testosterone undecanoate in the lipid and aqueous fractions of blood (testosterone undecanoate only measured in participants in the testosterone undecanoate arm). [0537] To assess the levels of intact testosterone undecanoate in serum for participants who received testosterone undecanoate. [0538] To compare testosterone concentrations in venous and capillary blood samples collected using the Mitra microsampling device with serum concentrations. [0539] To compare the concentrations of testosterone in saliva with serum concentrations. [0540] To evaluate the concentrations of androstenedione in saliva

Statistical Methods

[0541] Descriptive statistics (n, mean, standard deviation [SD], median and ranges for continuous variables, frequencies and percentages for categorical variables) were provided by treatment group and/or visit and sequence, if applicable. For PK parameters the geometric mean and the coefficient of variation were also presented. In each cohort, the primary PK endpoints were analysed in an analysis of variance (ANOVA) model corresponding to a 2-way cross-over design with factors for sequence, treatment, period and participant within sequence. The analyses were performed on the log-transformed values. The 90% confidence intervals (CIs) for the ratio of the treatment effects were calculated using the mean square error from the ANOVA model. The ratio was calculated for DITEST (test) versus testosterone undecanoate (standard). Safety and tolerability variables including vital signs, ECGs, AEs/SAEs, and laboratory variables, as well as demographic information (including age, BMI, weight and height), detailed medical history and current medical conditions were summarised in a descriptive manner only.

Demography and Baseline Characteristics:

[0542] In the overall safety set (N=25), participants had a mean age of 53.8 years (SD: 13.90), a mean body weight of 91.7 kg (SD: 13.04) and a mean BMI of 29.1 kg/m.sup.2 (SD: 3.70). Most participants were White (92.0%). Mean baseline serum testosterone was 3.00 nmol/L (SD: 2.59).

Pharmacokinetics

[0543] Testosterone: Serum testosterone levels were within the physiological range following dosing with DITEST (both doses in the fed state and at 200 mg in the fasted state) and testosterone undecanoate in the fed state. DITEST 120 mg had a lower C.sub.max and AUC.sub.0-10 compared to testosterone undecanoate and DITEST 200 mg had a similar C.sub.max and AUC.sub.0-10 compared to testosterone undecanoate. DITEST had an earlier T.sub.max compared to testosterone undecanoate. An exploratory comparison between the 2 DITEST doses (both in the fed state) showed a lower C.sub.max and AUC.sub.0-10 for the 120 mg dose compared to the 200 mg dose, suggesting dose proportionality. DITEST 200 mg showed the same C.sub.max and AUC.sub.0-10 when given fasted and fed, demonstrating no food effect on DITEST absorption.

[0544] DHT: DITEST was associated with lower serum concentrations of DHT compared to testosterone undecanoate. Mean serum DHT concentration remained below the upper limit of normal (2.65 nmol/L) for DITEST 120 mg.

[0545] Testosterone undecanoate: Serum testosterone undecanoate levels after dosing with 80 mg testosterone undecanoate were 10-fold greater than the testosterone levels, suggesting a large proportion of testosterone undecanoate was not converted to testosterone.

[0546] Aqueous and lipid fractions: The concentration-time curves for the aqueous and lipid fractions of testosterone were similar to serum levels for both DITEST and testosterone undecanoate, with the lipid fraction being approximately 1/10.sup.th of the serum concentration for both DITEST and testosterone undecanoate. In contrast, the lipid fraction of serum testosterone undecanoate made up over half the total serum measurement of testosterone undecanoate, suggesting that a large proportion of testosterone undecanoate resides in the lipid fraction.

[0547] Mitra micro sampling device: Venous sampling using the Mitra device showed similar but lower concentration-time curves for testosterone compared to when serum samples were used. The concentrations were higher, but still lower than the serum concentration, when the results were corrected for haematocrit values. Capillary testosterone levels measured using the Mitra device were 3 to 4-fold higher than when venous samples were measured with the Mitra device.

Safety

[0548] A total of 10 TEAEs were reported following DITEST (120 mg fed, 200 mg fed and 200 mg fasted) and 8 TEAEs were reported following testosterone undecanoate. The numbers of TEAEs were similar between DITEST and testosterone undecanoate and between fasted and fed states for DITEST. TEAEs were most commonly reported in the following SOCs: infections and infestations, skin and subcutaneous tissue disorders, and nervous system disorders.

[0549] One participant had QT prolongation after both doses of study intervention in Cohort 1 (testosterone undecanoate and DITEST 120 mg). The Investigator reported these findings as related to study intervention. All other TEAEs were reported as unrelated to study intervention. There were no SAEs or severe AEs following DITEST administration. One SAE was reported following testosterone undecanoate (severe urinary retention; not related to testosterone undecanoate). No participants discontinued due to AEs.

[0550] Mean changes in laboratory variables from pre-dose to 10 hours post-dose were small, with large standard deviations. Overall, there were no clinically relevant differences in clinical laboratory results between DITEST and testosterone undecanoate or between the fed and fasted states for DITEST.

[0551] Mean changes in vital signs were small (mean changes for DITEST between −2.1 and 4.3 mmHg for systolic blood pressure, between −5.5 and −0.3 mmHg for diastolic blood pressure, and between 2.8 and 10.5 bpm for heart rate, compared to mean changes of 12.8 mmHg, 1.5 mmHg and 8.5 bpm with testosterone undecanoate, respectively). No individual clinically significant abnormal findings were seen for any vital signs.

[0552] Serum testosterone levels were within the physiological range following dosing with DITEST in both the fed and fasted states and testosterone undecanoate in the fed state in adult male participants with primary or secondary hypogonadism. DITEST 120 mg had a lower C.sub.max and AUC.sub.0-10 compared to testosterone undecanoate and DITEST 200 mg had a similar C.sub.max and AUC.sub.0-10 compared to testosterone undecanoate. There was no food effect on C.sub.max and AUC.sub.0-10 for testosterone from DITEST. DITEST was associated with lower serum concentrations of DHT compared to testosterone undecanoate. Measurement of capillary testosterone using the Mitra micro sampling device and salivary testosterone showed very poor correlation with serum testosterone. There was no difference in the lipid fraction of testosterone between DITEST and testosterone undecanoate.

[0553] The FIGS. 1 to 2 and tables 3-5 illustrate the results of administration of dosing DITEST at 120 and 200 mg to men with hypogonadism. Using these results modelling of a dosing regimen predicts the average total testosterone over 24-hour (Cavg) and the minimum (Cmin) and maximum (Cmax) levels over 24 hours which are required for a clinician to prescribe the dosing regimen. Based on this a 70 kg man taking DITEST 200 mg with food every 12 hours will have Cmin 6.65, Cavg 15.00, Cmax 29.30 which would be acceptable levels for testosterone replacement and the dose could be up or down titrated by taking a sample at approximately 4 hours after dosing. DITEST was well tolerated when administered as single doses of 120 mg and 200 mg, with no serious or severe AEs. One participant had 2 AEs of ‘long QT syndrome’ that were reported as related to testosterone undecanoate and DITEST 120 mg, respectively. All other TEAEs were reported as unrelated to study intervention. There were no safety signals from the vital signs or clinical laboratory data. Thus, it can be concluded that DITEST shows potential for an oral native testosterone replacement with the advantage of no requirement for food or a high-fat meal to aid absorption.

REFERENCES

[0554] 1 C. J. MALKIN, P. J. PUGH, T. H. JONES and K. S. CHANNER, Testosterone for secondary prevention in men with ischaemic heart disease?, Q J Med 2003; 96:521-529 [0555] 2. Joseph M. Zmuda, M S, Paul D. Thompson, M D, Roberta Dickenson, B S, Linda L. Bausserman, PhD; Testosterone Decreases Lipoprotein(a) in Men; The American Journal of Cariology, Volume 77, Issue 14, June 1996, 1244-1247.