Preferred oral testosterone undecanoate therapy for achieving testosterone replacement therapy

Abstract

The present invention features, for example, novel testosterone undecanoate (TU) dosing regimens for testosterone replacement therapy. The TU may be formulated with a phytosterol or a phytosterol ester.

Description

[Background technology]

[0001] 2. Background of the Invention For testosterone replacement therapy (TRT) in hypogonadal men, the FDA imposes regulatory guidelines on testosterone (T) formulations to balance benefits and safety risks associated with abnormally high T concentrations (see, for example, Testosterone Replacement Therapy Advisory Committee Briefing Document, September 17, 2014, p. 13). These regulatory guidelines include a normal range of mean T serum concentration (Cavg) of 300-1000 ng / dL in 75% of subjects, a maximum T serum concentration (Cmax) of less than 1500 ng / dL in 85% of subjects, 1800-2500 ng / dL or less in 5%, and no more than 2500 ng / dL. These guidelines are the criteria used to obtain FDA approval, on which all pharmaceutical companies seeking to market testosterone replacement therapy will focus their research. To better manage benefits and safety risks, it is important to design formulations and dosing strategies to achieve favorable pharmacokinetic (PK) performance of testosterone or testosterone prodrugs such as testosterone undecanoate (TU). Therefore, novel formulations, dosing regimens and titration schemes are needed to meet these criteria and improve therapeutic efficacy. Summary of the Invention [Means for solving the problem]

[0002] Summary of the Invention The present invention features a novel testosterone undecanoate dosing strategy that involves performing plasma or serum measurements of testosterone and, if necessary, titrating the daily dose up or down to achieve favorable PK parameters.

[0003] In one aspect, the invention features a method of treating testosterone deficiency in a subject in need thereof. The subject to be treated is a male, e.g., a hypogonadal male. The method includes carrying out a treatment regimen that includes administering to the subject a pharmaceutical composition that includes testosterone undecanoate (TU), a non-sterol solubilizer effective for solubilizing TU, and a phytosterol or phytosterol ester. About 400 mg of TU can be administered, for example, at the beginning of the treatment regimen. The method can include establishing a first steady-state serum concentration of testosterone. The method can include providing a first serum value of testosterone in the subject after administration of TU. In addition, the method can further include, for example, carrying out a first titration of testosterone undecanoate as needed. If the first serum value of testosterone is less than about 400 / F or less than 400 / F+b ng / dL (e.g., a serum concentration less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration less than about 400 ng / dL), the daily dosage can be increased, for example, to about 600 mg TU, where F corresponds to a predefined empirical factor related to plasma and serum concentration and is described in more detail below. This can establish a second steady-state serum value of testosterone that is higher than the first steady-state serum value of testosterone. When the first serum value of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449ng / dL to about 1011ng / dL or about 460ng / dL to about 971ng / dL or a plasma concentration of about 400ng / dL to about 900ng / dL), the daily dosage can be maintained. This allows the first steady-state serum value of testosterone to be maintained. When the first serum value of testosterone is more than about 900 / F ng / dL or more than 900 / F+b ng / dL (e.g., a serum concentration of more than about 1011ng / dL or more than about 971ng / dL or a plasma concentration of more than about 900ng / dL), the daily dosage can be reduced, for example, to about 200mg TU. This may establish a second steady state serum level of testosterone that is lower than the first steady state serum level of testosterone.

[0004] In another aspect, the invention features a method of treating testosterone deficiency in a subject in need thereof. The subject to be treated can be a male, for example a hypogonadal male. The method includes performing a treatment regimen that includes administering to the subject a pharmaceutical composition that includes testosterone undecanoate (TU), a non-sterol solubilizer effective to solubilize the TU, and a phytosterol or phytosterol ester. About 400 mg of TU can be administered, for example, at the beginning of the treatment regimen. The method can include establishing a first steady-state serum concentration of testosterone. The method can include providing a first serum value of testosterone in the subject after administration of the TU. In addition, the method can further include, for example, performing a first titration of testosterone undecanoate as needed. If the first serum value of testosterone is less than about 460 ng / dL, the daily dosage can be increased, for example, to about 600 mg of TU. This can establish a second steady-state serum value of testosterone that is higher than the first steady-state serum value of testosterone. If the first serum value of testosterone is between 460 ng / dL and about 971 ng / dL, the daily dosage may be maintained. This may maintain a first steady-state serum value of testosterone. If the first serum value of testosterone is greater than about 971 ng / dL, the daily dosage may be increased, for example, to about 200 mg TU. This may establish a second steady-state serum value of testosterone that is lower than the first steady-state serum value of testosterone. The subject may, for example, be on antihypertensive therapy and may exhibit a mean change in systolic blood pressure of 3.4 mmHg or less, a mean change in diastolic blood pressure of 1.8 mmHg or less, and / or a mean change in heart rate of 1.3 beats per minute or less. The subject may have diabetes mellitus and may exhibit a mean change in systolic blood pressure of 3.0 mmHg or less, a mean change in diastolic blood pressure of 1.7 mmHg or less, and / or a mean change in heart rate of 1.9 beats per minute or less.

[0005] The serum level of testosterone may be measured about 3 hours to about 6 hours (e.g., 3 hours, 4 hours, 5 hours, or 6 hours, e.g., about 3 hours to about 5 hours) after administration. The serum level of testosterone may be measured about 3 hours to about 5 hours after administration. The pharmaceutical composition may be administered with a meal. The pharmaceutical composition may be administered in two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses. The pharmaceutical composition may be administered in two doses per day (e.g., twice daily administration). The pharmaceutical composition may be administered in three doses per day. A first dose may be administered in the morning, and a second dose may be administered in the evening. The first dose may include about 200 mg of TU, ​​and the second dose may include about 200 mg of TU.

[0006] In some embodiments, after the first titration, the daily dosage may be increased to about 600 mg TU, with the first dose containing about 300 mg TU and the second dose containing about 300 mg TU; the daily dosage may be maintained at about 400 mg TU, with the first dose containing about 200 mg TU and the second dose containing about 200 mg TU; or the daily dosage may be decreased to about 200 mg TU, with the first dose containing about 100 mg TU and the second dose containing about 100 mg TU.

[0007] In some embodiments, a second serum level of testosterone may be measured.

[0008] In some embodiments, the second titration may be performed, for example, after a second serum testosterone measurement.

[0009] The first serum level of testosterone can be less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration of less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration of less than about 400 ng / dL), and the daily dosage can be increased to about 600 mg TU, thereby establishing a third steady-state serum level of testosterone that is higher than the second steady-state serum level of testosterone. The first serum level of testosterone may be about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), and the dosage may be maintained. This may maintain a second steady-state serum level of testosterone. The first serum level of testosterone may be greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration of greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration of greater than about 900 ng / dL), and the dosage may be reduced to about 200 mg TU. This may establish a third steady state serum level of testosterone that is lower than the first steady state serum level of testosterone.

[0010] After the first titration, about 600 mg of TU can be administered to the subject daily. If the second serum level of testosterone is less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration of less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration of less than about 400 ng / dL), the method can include orally administering about 800 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is higher than the second steady-state serum level of testosterone. If the second serum level of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), the method can include continuing to orally administer about 600 mg of TU to the subject daily to maintain the second steady state serum level of testosterone. If the second serum value of testosterone is greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration greater than about 900 ng / dL), the method can include orally administering about 400 mg of TU to the subject daily to establish a third steady-state serum value of testosterone that is lower than the second steady-state serum value of testosterone.

[0011] After the first titration, about 400 mg of TU can be administered to the subject daily. If the second serum level of testosterone is less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration less than about 400 ng / dL), the method can include orally administering about 600 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is higher than the second steady-state serum level of testosterone. If the second serum level of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), the method can include continuing to orally administer about 400 mg of TU to the subject daily to maintain the second steady state serum level of testosterone. If the second serum value of testosterone is greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration greater than about 900 ng / dL), the method can include orally administering about 200 mg of TU to the subject daily to establish a third steady-state serum value of testosterone that is lower than the second steady-state serum value of testosterone.

[0012] After the first titration, about 200 mg of TU can be administered to the subject daily. If the second serum level of testosterone is less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration of less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration of less than about 400 ng / dL), the method can include orally administering about 400 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is higher than the second steady-state serum level of testosterone. If the second serum level of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), the method can include continuing to orally administer about 200 mg of TU to the subject daily to maintain the second steady state serum level of testosterone. If the second serum level of testosterone is greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration greater than about 900 ng / dL), the method can include orally administering about 100 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is lower than the second steady-state serum level of testosterone.

[0013] In some embodiments, after the second titration, the dosage may be increased to about 800 mg TU, with the first dose containing about 400 mg TU and the second dose containing about 400 mg TU. In some embodiments, the dosage may be decreased to about 100 mg TU, with the subject receiving a single dose of about 100 mg TU. The single dose of about 100 mg TU may be administered in the morning.

[0014] The first serum value of testosterone may be measured after steady state is reached. For example, the first serum value of testosterone may be measured before day 21, for example, from about day 1 to about day 21 of the treatment regimen (e.g., day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21, e.g., day 14). The first serum value of testosterone may be measured from about day 30 to about day 60 of the treatment regimen (e.g., day 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60).

[0015] The first titration can be performed any time after the first serum level of testosterone is measured, for example, from about day 1 to about day 35, for example, from about day 7 to about day 35, for example, from about day 21 to about day 35 (e.g., day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35, for example, day 28) of the treatment regimen. The first titration may be performed on about day 30 to about day 60 (e.g., day 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60) of the treatment regimen.

[0016] For example, the first serum level of testosterone may be measured on about day 14 of the treatment regimen, and / or the first titration may be performed on about day 28 of the treatment regimen.

[0017] A second serum level of testosterone can be measured. For example, the second serum level of testosterone can be measured at about day 35 to about day 49 (e.g., day 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, e.g., day 42) of the treatment regimen.

[0018] The second titration can be performed, for example, after a second serum value of testosterone measurement. The second titration can be performed on about day 49 to about day 63 (e.g., day 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 63, e.g., day 56) of the treatment regimen. For example, a second serum value of testosterone can be measured on about day 42, and the second titration can be made on about day 56.

[0019] In some embodiments, the first titration may be performed on about day 28 of the treatment regimen, and / or the second titration may be performed on about day 56 of the treatment regimen.

[0020] In some embodiments, the first titration may be performed, for example, on about day 21 to about day 35 (e.g., day 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, e.g., day 28) of the treatment regimen. After the first titration, a second steady-state serum value of testosterone may be established. A second serum value of testosterone may then be measured. A second titration may then be performed.

[0021] The subject has not previously been administered TU or other testosterone replacement therapy (e.g., a prodrug of TU) for a period of at least 7 days (e.g., 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year or more), e.g., the period may be sufficient to flush all exogenous testosterone from the body.

[0022] In some embodiments, the methods are performed on a population of human subjects. The population of subjects can include, for example, at least 10 subjects, at least 50 subjects, at least 100 subjects, at least 200 subjects, at least 500 subjects, or more subjects.

[0023] In some embodiments, the method achieves a serum normal range Cavg of about 300 ng / dL to about 1000 ng / dL in at least 75% of the population; achieves a Cmax of less than about 1500 ng / dL in at least 85% of the population; achieves a Cmax of about 1800 ng / dL to about 2500 ng / dL in 5% or less of the population; and / or achieves a Cmax of greater than about 2500 ng / dL in 0% or less of the population.

[0024] In some embodiments, the methods reduce the average number of incorrect dosings or the risk of incorrect dosing per subject in a population to achieve steady state testosterone serum levels of about 300 ng / dL to about 1000 ng / dL for a population receiving a treatment regimen where the initial dose is not about 400 mg TU and / or where serum levels are not measured about 3 hours to about 6 hours after dosing.

[0025] In some embodiments, the method achieves a serum normal range Cavg of about 300 ng / dL to about 1000 ng / dL in a greater number of subjects in the population compared to a treatment regimen in which the initial dose is not about 400 mg TU and / or serum values ​​are not measured about 3 hours to about 6 hours after administration; a Cavg of less than about 1500 ng / dL in a greater number of subjects in the population compared to a treatment regimen in which the initial dose is not about 400 mg TU and / or serum values ​​are not measured about 3 hours to about 6 hours after administration. achieves a Cmax of about 1800 ng / dL to about 2500 ng / dL in a smaller number of subjects in the population compared to a treatment regimen in which the initial dose is not about 400 mg TU and / or serum levels are not measured at about 3 to about 6 hours after administration; and / or achieves a Cmax of greater than about 2500 ng / dL in a smaller number of subjects in the population compared to a treatment regimen in which the initial dose is not about 400 mg TU and / or serum levels are not measured at about 3 to about 6 hours after administration.

[0026] In some embodiments, the method reduces the risk of elevated blood pressure, for example, in a population of human subjects. For example, in some embodiments, the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure does not increase by more than about 5 mmHg compared to baseline (e.g., about 4, 3, or 2 mmHg or less). In some embodiments, the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure does not increase by more than about 3 mmHg compared to baseline. In some embodiments, the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure does not increase by more than about 2 mmHg compared to baseline when measured by ambulatory blood pressure monitoring (ABPM). In some embodiments, the subject is diabetic or hypertensive, and the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure does not increase by more than about 4 mmHg compared to baseline when measured by ambulatory blood pressure monitoring (ABPM).

[0027] In some embodiments, the population mean has a Cmax / Cavg ratio from 0 to 24 hours of less than 2.5; a Cmax / Cavg ratio from 0 to 12 hours of less than 2.2; and / or a Cmax / Cavg ratio from 12 to 24 hours of less than 2.2.

[0028] The pharmaceutical composition may comprise about 5% to about 40% by weight (e.g., about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, e.g., about 18.2% by weight) of TU. The pharmaceutical composition may comprise about 2% to about 45% by weight (e.g., about 2%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or about 45% by weight, e.g., about 25% by weight) of phytosterol or phytosterol ester. The phytosterol may comprise a phytosterol, a phytosterol ester, or a combination thereof. The pharmaceutical composition may comprise a phytosterol ester. The formulation may comprise about 10% to about 90% by weight (e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% by weight) of a non-sterol solubilizer. The non-sterol solubilizer may be selected from lipids, surfactants (e.g., hydrophobic and / or hydrophilic surfactants) and mixtures thereof. The pharmaceutical composition may be self-emulsifying or self-microemulsifying.

[0029] In some embodiments, the non-sterol solubilizer comprises propylene glycol monolaurate.

[0030] In some embodiments, the non-sterol solubilizer comprises polyoxyl 40 hydrogenated castor oil.

[0031] In some embodiments, the pharmaceutical composition comprises about 10% to about 25% by weight (e.g., about 15% by weight, 20% by weight, or 25% by weight, e.g., about 18.2% by weight) of solubilized testosterone undecanoate; about 5% to about 40% by weight (e.g., about 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, or 40% by weight, e.g., about 15% by weight) of a hydrophilic surfactant; about 15% to about 65% by weight (e.g., about 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, %, 50%, 55%, 60% or 65% by weight, e.g., about 39.9% by weight, of a hydrophobic surfactant; about 2% to about 45% by weight (e.g., about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% by weight, e.g., about 25% by weight) of a phytosterol ester; and about 0 to about 15% by weight (e.g., about 1%, 2%, 3%, 4%, 5%, 10% or 15% by weight, e.g., about 2% by weight) of a solubilizing agent.

[0032] In some embodiments, the oral formulation comprises from about 10% to about 40% by weight (eg, from about 10% to about 30%, eg, about 25% by weight) of one or more phytosterol esters.

[0033] In some embodiments, the solubilizing agent comprises dl-alpha-tocopherol and / or its esters or acetates.

[0034] In some embodiments, the pharmaceutical composition comprises about 18.2% by weight solubilized testosterone undecanoate; about 15.0% by weight polyoxyl 40 hydrogenated castor oil; about 39.9% by weight propylene glycol monolaurate; about 25.0% by weight one or more phytosterol esters; and about 2.0% by weight dl-alpha-tocopherol and / or its esters or acetates.

[0035] In some embodiments of any of the above aspects, the first serum value and / or the second serum value are measured by measuring the testosterone concentration in serum that has been allowed to clot at room temperature for about 30 minutes prior to centrifugation in a tube, measuring the testosterone concentration of plasma in a tube supplemented with EDTA and NaF, and multiplying the testosterone concentration by the reciprocal of a predefined coefficient F (1 / F), or an equivalent method. The predefined coefficient can be, for example, about 0.70 to about 1.10, e.g., about 0.81 to about 0.94 (e.g., 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, or 0.94). For example, the default factor may be 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, or 1.10. In one embodiment, the default factor is 0.82. In one embodiment, the default factor is 0.83. In one embodiment, the default coefficient is 0.88. In one embodiment, the default coefficient is 0.89. In another embodiment, the default coefficient is 0.92.

[0036] In some embodiments of any of the above aspects, the subject is at risk for high blood pressure, heart attack, or stroke.

[0037] The subject may suffer from low testosterone levels due to aging.

[0038] The subject may be suffering from low testosterone levels due to a disease that reduces testosterone production.

[0039] The subject may have diabetes (eg, diabetes mellitus), hypertension, a metabolic disorder, or is obese.

[0040] In some embodiments, the subject has been or is being treated with an antihypertensive medication.

[0041] The subject may have osteoporosis, decreased sexual function or libido, muscle strength or endurance, aplastic anemia, AIDS wasting syndrome, obstructive sleep apnea, metabolic disorders, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

[0042] The subject may be at risk for adverse events associated with testosterone (eg, elevated blood pressure).

[0043] definition As used herein, the term "about" refers to a value that is + / - 10% of the recited value. For example, a dose of about 400 mg TU refers to a dose containing 360 mg to 440 mg TU. When referring to days, the term about refers to a value of + / - 3 days. For example, an event (e.g., serum T measurement or dose titration) that occurs about day 14 may occur between day 11 and day 17.

[0044] As used herein, the term "phytosterol" refers to a group of plant sterol molecules that are naturally occurring compounds found in plant cell membranes. Phytosterols include both plant sterols and stanols. Phytosterols can be derived from any common plant source, such as soybean, wood, tall oil, vegetable oils, etc. Phytosterols include, for example, β-sitosterol, campesterol, stigmasterol, stigmastanol, campestanol, brassicasterol, ergosterol, lupeol, cycloartenol, etc. Phytosterol also encompasses its esterified derivatives, which may be referred to as phytosterol esters or phytostanol esters. Phytosterol esters are derived from long chain (e.g., C6-C8) sterols such as octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. 24 , for example C 10 ~C 24 , for example C14 ~C 24 Phytosterols are phytosterols esterified with fatty acids such as β-sitosterol, ... Phytosterols derived from tall oil may contain about 36-79% sitosterol, about 6-34% sitostanol, about 4-25% campesterol and about 0-14% campestanol. Phytosterols derived from wood may contain about 72% sitosterol, about 8.2% campesterol, about 0.3% stigmasterol, about 0% brassicasterol, about 15.3% sitostanol and about 1.6% campestanol. Phytosterols derived from vegetable oil may contain about 45% sitosterol, about 26.8% campesterol, about 19.3% stigmasterol, about 1.6% brassicasterol, about 2.1% sitostanol and about 0.8% campestanol. Pharmaceutical compositions containing phytosterols or their esters may contain one or more of the aforementioned ingredients or mixtures thereof. As used herein, the term "phytosterol" or "phytosterols" encompasses both phytosterols and phytosterol esters.

[0045] As used herein, "titration" refers to increasing or decreasing the total daily dose of testosterone undecanoate administered to a subject, typically based on the subject's response to exogenously administered testosterone undecanoate. The dose may be increased or decreased based on measurements of serum testosterone concentrations after steady state is reached.

[0046] As used herein, "steady state" refers to the achievement of a stable response in serum total testosterone levels to exogenously administered testosterone undecanoate, typically reached at least 7 days (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 28 days) after the initiation of a dosing regimen.

[0047] In some embodiments, titration may also include adjusting the manner in which the total dose is administered, such as whether it is administered as two or three doses within a 24 hour period, whether it is administered with a meal, whether it is administered with a meal having a particular fat content, or whether it is administered at a particular time of day.

[0048] The terms "plasma testosterone concentration" and "serum testosterone concentration" refer to "total" testosterone concentration, which is the total amount of bioavailable testosterone, including free and protein-bound testosterone concentrations, in plasma and serum, respectively. As with any bioanalytical measurement, to promote consistency, the method utilized to measure initial serum testosterone levels should be consistent with the method used to monitor and remeasure serum testosterone levels during the subject's clinical examination and testosterone therapy.

[0049] As used herein, the mean plasma or serum testosterone concentration may be determined using methods and practices known in the art. For example, the mean baseline plasma or serum testosterone concentration of a human male is the arithmetic mean of the total plasma or serum testosterone concentration, respectively, determined at at least two consecutive time points reasonably spaced apart from each other, for example, from about 1 hour to about 168 hours apart. In one example, the serum or plasma testosterone concentration may be determined at at least two consecutive time points, from about 12 hours to about 48 hours apart. In another example, the plasma or serum testosterone concentration of a human male may be determined at about 5:00 to about 11:00 in the morning. Additionally, the plasma or serum testosterone concentration may be determined by standard analytical procedures and methods available in the art, such as, for example, automated or manual immunoassay methods, liquid chromatography or liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0050] As used herein, the term "serum value" refers to a specified Cavg serum concentration testosterone and the corresponding plasma testosterone concentration. The serum concentration is multiplied by a predefined factor (F) to convert the serum concentration to the corresponding plasma concentration, thereby: F*(serum concentration) = plasma concentration; and Serum value = serum concentration = (1 / F)*(plasma concentration) Since serum and plasma measurements of testosterone yield different values ​​depending on the assay used for the measurement, a predefined coefficient F is required to relate measurements using different assays. The predefined coefficient is empirically calculated and can be, for example, about 0.70 to about 1.10, for example, about 0.81 to about 0.94 (e.g., 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, or 0.94). The predefined coefficients can be 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, or 1.10. In one particular embodiment, the predetermined coefficient is about 0.89 when the plasma measurement is performed using a plasma sample tube containing NaF / EDTA. In this embodiment, a serum value of about 300 ng / dL refers to a serum concentration of testosterone of about 300 ng / dL and a NaF / EDTA plasma concentration of testosterone of about 267 ng / dL (300 multiplied by 0.89 ng / dL). A serum value of about 1000 ng / dL refers to a serum concentration of testosterone of about 1000 ng / dL and a NaF / EDTA plasma concentration of testosterone of about 1000 multiplied by 0.89 ng / dL, which is about 890 ng / dL. The NaF / EDTA plasma concentrations of testosterone used as cutoffs for titration determination of 400 ng / dL and 900 ng / dL may refer to serum values ​​of (400 / 0.89)=449 ng / dL and (900 / 0.89)=1011 ng / dL, respectively. Those skilled in the art will appreciate that due to empirically derived coefficients and associated errors, these values ​​may vary within reasonable error, for example, about + / - 0 10%.Serum values ​​can be obtained by measuring testosterone concentration in serum that has been allowed to clot at room temperature for about 30 minutes before centrifugation in tubes, measuring plasma testosterone concentration in tubes supplemented with EDTA and NaF, and multiplying the testosterone concentration by a predefined factor F, or an equivalent method. Exemplary methods are described, for example, in Lachance et al. Future Sci OA, FSO55, 2015, which is incorporated herein by reference in its entirety.

[0051] In another embodiment, linear regression is used to derive an equation that can be used to relate serum and plasma concentrations, thereby: F*(serum concentration-b)=plasma concentration; and Serum value = serum concentration = (1 / F)*(plasma concentration)+b where b is the y-intercept in the linear regression and 1 / F is the slope. Because serum and plasma measurements of testosterone yield different values ​​depending on the assay used for measurement, a predefined linear equation is required to relate measurements using different assays. For example, the slope 1 / F may be 1.023 and the intercept may be 50.45 ng / dL. In one particular embodiment, the predefined slope is about 1.023 and the intercept is 50.45 ng / dL when the plasma measurement is performed using a plasma sample tube containing NaF / EDTA. In this embodiment, a serum value of about 300 ng / dL refers to a serum concentration of testosterone of about 300 ng / dL and a NaF / EDTA plasma concentration of testosterone of about 244 ng / dL (300 minus the intercept 50.45 and dividing the result by 1.023). A serum value of about 1000ng / dL refers to a serum concentration of testosterone of about 1000ng / dL and a NaF / EDTA plasma concentration of testosterone of about 928ng / dL (1000 minus the intercept 50.45 and divide the result by 1.023). A NaF / EDTA plasma concentration of testosterone used as a cutoff for titration determination of 400ng / dL and 900ng / dL may refer to serum values ​​of (400*1.023)+50.45=460ng / dL and (900*1.023)+50.45=971ng / dL, respectively (see, e.g., FIG. 8). Those skilled in the art will understand that due to empirically derived coefficients and associated errors, these values ​​may vary within a reasonable error of, for example, about + / - 10%. Serum values ​​can be obtained by measuring testosterone concentration in serum that has been allowed to clot at room temperature for approximately 30 minutes before centrifugation in tubes, measuring plasma testosterone concentration in tubes supplemented with EDTA and NaF, and converting to serum values ​​using a linear equation, or an equivalent method.

[0052] One skilled in the art will also appreciate that the parameters of the linear equation used may depend on the analytical methodology of the assay for testosterone. For example, immunoassays may differ in selectivity and similarly yield suitable parameters for relating serum and plasma concentrations.

[0053] In addition, one of skill in the art will appreciate that more sophisticated equations relating serum and plasma concentrations can be applied to the empirical relationship, for example, non-linear equations could be used to describe the relationship between serum and plasma concentrations.

[0054] As used herein, AUC 0-t The term is the area under the curve of the plasma versus time graph determined for the analyte from time 0 to time "t".

[0055] As used herein, the term "Cavg" or "C avg-t " is AUC 0-t is determined as C divided by a given time period (t). For example, avg-8h is the AUC 0-8 The mean plasma concentration over an 8 hour period after dosing is determined by dividing the C value by 8. avg-12h is the AUC 0-12 is the average plasma concentration over a 12-hour period after dosing, determined by dividing C by 12; avg-24h is the AUC 0-24 The mean plasma concentration over a 24-hour period after dosing is determined, for example, by dividing the C value by 24. avg The value is C avg-24h It is considered that.

[0056] As used herein, "C t " refers to the serum concentration of testosterone at time "t" before or after administration of a dose of the invention. Time "t" is generally in hours unless otherwise specified. For example, C (-2~0) C tC refers to the serum testosterone concentration measured in a sample collected at a time between about 2 hours and immediately prior to administration of the dose to the subject being tested. (2~4) C t refers to the serum testosterone concentration measured in a sample collected at a time between about 2 hours and 4 hours following administration of the dose to the subject being tested.

[0057] As used herein, a PK parameter (e.g., Cavg or Cmax) may be a parameter measured in a population of subjects treated, e.g., with a TU formulation, e.g., as part of a clinical trial.

[0058] As used herein, a "population of subjects" refers to a group of at least 10 subjects (e.g., at least 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500 or more).

[0059] As used herein, "subject" refers to an animal, such as a human subject. The subject may be a male. The subject may be a hypogonadal male. The subject may have or be at risk of developing high blood pressure, heart attack, or stroke. The subject may suffer from low T levels due to aging. The subject may suffer from low testosterone levels due to a disease that reduces testosterone production. The subject may have comorbidities, such as diabetes (e.g., diabetes mellitus), hypertension, and / or obesity. The subject may have been or is being treated with antihypertensive medication. The subject may have a metabolic disorder, for example, when obesity, hypertension, and reduced insulin sensitivity coexist. The subject may be identified from a titration protocol for testosterone replacement therapy. The subject may have osteoporosis, decreased sexual function or libido, muscle strength or endurance, aplastic anemia, AIDS wasting syndrome, obstructive sleep apnea, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). [Brief description of the drawings]

[0060] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Illustrative diagram of Study 1 SOV2012-F1 dose finding in the study. Abbreviations: am = morning; N = number of subjects; pm = evening; T3-5 = plasma testosterone concentration measured 3-5 hours (+10 min) after the morning dose. a The investigator and sponsor will review the data for each individual and reasons for non-response to treatment will be investigated. Assuming correct compliance with the study drug, SOV2012-F1 may be increased to 600 mg am, 400 mg pm at the investigator's discretion while taking safety into account, or the subject may be discontinued from the study as a non-responder. Data will be reported in the clinical trial report. [Diagram 2] 1 is a graph showing the theoretical results (accurate or inaccurate) of titration decisions using a single blood draw at various time points including 0, 1.5, 3, 4, 5, 6, 8, 10 or 12 hours after a morning dose to predict 24 hour T compared to the calculated 24 hour T. To illustrate the approach, this figure uses the commonly accepted serum normal T range of 300-1000 ng / dL. [Diagram 3] Graph showing percentage of subjects at each time point and the use of blood draws will lead to accurate dosing determinations (Days 7 and 14 based on 24 hour T Cavg). [Figure 4] Graph showing percentage of incorrect dosing based on a single blood draw (Day 7 and Day 14). [Diagram 5] Graph showing percentage of subjects at each time point and the use of blood draws will lead to accurate dosing determinations (Days 7 and 14 based on Cmax 0-12). [Figure 6] 1 is a schematic flow chart illustrating the titration algorithm as described herein. [Figure 7] 1 is a graph showing the mean plasma T concentrations from 0 to 6 hours after administration on days 14 and 42. [Figure 8]1 is a regression plot of serum versus plasma concentrations using serum-plasma concentration pairs obtained 3 to 5 hours after the morning dose. [Figure 9A] FIG. 1 is a graph showing hourly ambulatory blood pressure (BP) results at baseline and 120 and 180 days after initiating oral testosterone undecanoate therapy. Ambulatory systolic BP is shown. [Figure 9B] FIG. 1 is a graph showing hourly ambulatory blood pressure (BP) results at baseline and 120 and 180 days after initiating oral testosterone undecanoate therapy. Ambulatory diastolic BP is shown. [Figure 10A] Graph showing cumulative distribution function of percentage change in ambulatory blood pressure from baseline to days 120 and 180. Ambulatory systolic BP. [Figure 10B] Graph showing cumulative distribution function of percentage change in ambulatory blood pressure from baseline to days 120 and 180. Ambulatory diastolic BP. [Figure 11] FIG. 1 is a graph showing the association between serum hemoglobin (g / L) at day 90 of treatment and ambulatory systolic BP at day 120 of treatment. A weakly significant positive correlation was observed. [Figure 12] 1 is a graph showing the evaluation between serum testosterone concentrations and changes in ambulatory systolic BP on day 120 of treatment. No correlation was observed. [Figure 13] FIG. 1 is a graph showing plasma T from 0 to 24 hours. [Figure 14] FIG. 1 is a graph showing plasma T with standard deviation (SD) from 0 to 24 hours. [Figure 15] Graph showing plasma and serum T from 0 to 24 hours. [Figure 16] Graph showing plasma TU from 0 to 24 hours. [Figure 17] Graph showing plasma TU with standard deviation (SD) from 0 to 24 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] Detailed Description The present invention features novel methods for treating testosterone deficiency. In particular, the present invention features a testosterone undecanoate (TU) dosing regimen that includes administration of TU, ​​performing plasma or serum measurements of testosterone (T), and titrating (e.g., increasing or decreasing) the dose as needed to achieve favorable pharmacokinetic (PK) parameters. Favorable PK parameters may be achieved without titrating the dose. Obtaining favorable PK parameters is necessary to obtain FDA approval for testosterone replacement therapy. Currently, FDA guidelines for testosterone replacement therapy require a normal range of testosterone serum concentrations (Cavg) of 300-1000 ng / dL in 75% of subjects, a maximum T serum concentration (Cmax) of less than 1500 ng / dL in 85% of subjects, 1800-2500 ng / dL in 5% or less, and no more than 2500 ng / dL. Please note that the FDA guidelines are really guidelines, and those skilled in the art will understand that they may be changed or become less strict.For example, another commonly accepted definition of normal range is about 264ng / dL to about 917ng / dL.Furthermore, some subjects may actually show serum Cmax above 2500ng / dL.However, the goal is to have as few subjects as possible exceed this threshold.

[0062] In general, the goal is to design a dosing strategy that simplifies administration, improves patient compliance, and provides a safe and effective therapy while reducing the number of titrations and serum T measurements to obtain serum T concentrations in a range consistent with normal subjects (e.g., non-hypogonadal males) and reflective of FDA guidelines. Furthermore, when titration is performed, it is also desirable to make accurate titration decisions so that the dosage does not need to be adjusted one or more times. For example, if a dose of TU is administered and a serum T concentration below the normal range is measured, it may be desirable to increase the dosage. However, if the dosage is increased too much and the next serum T concentration measurement is above the normal range, it may be necessary to decrease the dosage. An additional goal is to reduce the unwanted side effects associated with testosterone replacement therapy, such as elevated blood pressure. The methods described herein have been shown to meet the aforementioned goals by minimizing the elevated blood pressure that can occur with testosterone replacement therapy and reducing inaccurate titration decisions.

[0063] The invention also features a method of treating a subject undergoing testosterone replacement therapy at risk for adverse events related to testosterone, such as elevated blood pressure and heart rate. The subject may have or be at risk of developing hypertension, heart attack, or stroke. The subject may suffer from low T levels due to aging. The subject may suffer from low testosterone levels due to a disease that reduces testosterone production. The subject may have a comorbidity, such as diabetes (e.g., diabetes mellitus), hypertension, and / or obesity. The subject may have been or is being treated with antihypertensive medication. The subject may have a metabolic disorder, for example, when obesity, hypertension, and reduced insulin sensitivity are coexisting. The subject may be identified from a titration protocol for testosterone replacement therapy. The subject may have osteoporosis, decreased sexual function or libido, muscle strength or endurance, aplastic anemia, AIDS wasting syndrome, obstructive sleep apnea, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

[0064] Surprisingly, the inventors have discovered that using the starting dose of TU described herein, measuring serum or plasma concentrations of T about 3 hours to about 5 hours after the administration event, and titrating the dose of TU within a predefined range after the plasma or serum measurement leads to improved PK performance, more accurate titration decisions, less inaccurate titration decisions, and a reduced risk of elevated blood pressure and / or heart rate in treated subjects. Furthermore, having titration decisions made using a NaF / EDTA plasma Cavg concentration range of about 400 ng / dL to about 900 mg / dL (e.g., a serum Cavg concentration range of about 449 ng / dL to about 1011 ng / dL when F is 0.89 or about 460 ng / dL to about 971 ng / dL, a slope 1 / F is 1.023, and b is 50.45) may result in more favorable outcomes compared to a Cavg concentration range of about 300 ng / dL to about 1000 ng / dL. The preferred starting dose of TU and the specific days for carrying out serum or plasma measurement and performing dose titration are described in more detail below.More surprisingly, the inventors have discovered that this treatment regimen results in a reduced risk of elevated blood pressure and heart rate.This may eliminate the need for subsequent blood pressure or heart rate medication required by subjects undergoing testosterone replacement therapy.

[0065] Additionally, the inventors have also discovered that testosterone levels are reliably measured in a time frame of about 3 hours to about 6 hours (e.g., about 3 hours to about 5 hours) after administration of the TU formulation (e.g., after a morning dose). This time frame provides a robust measurement time frame for single measurement assessment. This feature may be due to the phytosterol esters in the formulation, e.g., the presence of a flat PK curve after administration, e.g., modified release, allowing reliable assessment of subjects within the sample time frame (see FIG. 7). Providing a reliable time frame in this range provides reliable dosing decisions and results, leading to more accurate dosing decisions and potentially reducing unwanted side effects such as elevated blood pressure and increased heart rate.

[0066] Dosage and Administration Described herein are formulations and methods for oral administration of testosterone undecanoate. Orally administered formulations (e.g., capsules, softgels, tablets, lozenges, syrups, etc.) can be used to treat subjects (e.g., humans, e.g., male human subjects). The subjects may suffer from testosterone deficiency, such as hypogonadism. Thus, the methods described herein can be used to determine a target serum testosterone concentration C for a subject (e.g., male subject) or a population of subjects. ave The method includes orally administering to a subject a pharmaceutical composition containing a dosage of TU, ​​resulting in a serum concentration of testosterone within the range.

[0067] The formulation may contain TU at about 5% by weight to about 40% by weight (e.g., about 5% by weight to about 35% by weight, about 5% by weight to about 25% by weight, about 5% by weight to about 20% by weight, about 10% by weight to about 35% by weight, about 10% by weight to about 25% by weight, about 10% by weight to about 20% by weight, about 10% by weight to about 15% by weight, about 15% by weight to about 35% by weight, about 15% by weight to about 30% by weight, about 15% by weight to about 25% by weight, about 15% by weight to about 20% by weight) (wt%) of the formulation. For example, the formulation may contain about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 29% or 40% by weight of the formulation. The pharmaceutical composition may provide a daily dosage of TU of about 25 mg to about 1000 mg (e.g., about 50 mg to about 600 mg, about 100 mg to about 600 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 100 mg to about 200 mg). For example, a formulation may provide about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg or 1000 mg of TU per day.

[0068] Pharmaceutical composition can be administered in multiple doses.For example, it is understood that all doses can be given continuously or divided into multiple doses for each given time frame.For example, a daily dose of about 400mg can be administered in two doses (for example, a first dose of about 200mg and a second dose of about 200mg, or a first dose of 100mg and a second dose of about 300mg).

[0069] The pharmaceutical compositions described herein can be administered one or more times per day. For example, a dose can be administered once a day, twice a day, three times a day, four times a day, five times a day, six times a day or more. The formulation can be administered with food.

[0070] Formulations and excipients The formulations used in the methods described herein are provided in self-emulsifying drug delivery system (SEDDS), self-microemulsifying drug delivery system (SMEDDS) or self-nanoemulsifying drug delivery system (SNEDDS) delivery systems, which are known in the art as useful mechanisms for the delivery of hydrophobic drugs such as TU. Hydrophobic drugs are associated with poor water solubility and low oral bioavailability. SEDDS / SMEDDS / SNEDDS formulations are isotropic mixtures of oil, surfactant, co-surfactant (or solubilizer) and drug. The basic principle of this system is its ability to form fine oil-in-water (o / w) microemulsions under gentle agitation (e.g., digestive motility of the stomach and intestinal tract provides the agitation required for self-emulsification in vivo in the intestinal lumen) after dilution with an aqueous phase. This spontaneous formation of emulsions in a liquid environment such as the gastrointestinal tract presents the drug in a solubilized form, and the small size of the formed droplets provides a large interfacial surface area for drug absorption. In addition to solubilization, the presence of lipid in the formulation further promotes the improvement of bioavailability by affecting drug absorption.The selection of suitable self-emulsifying formulation depends on the evaluation of the solubility of drug in various components, the area of ​​self-emulsifying region as obtained in phase diagram, the droplet size distribution of the emulsion obtained after self-emulsification and the release rate of drug after dispersion in intestinal fluid.

[0071] The formulations described herein include a TU. The TU may be formulated with a non-sterol solubilizer and one or more phytosterols or phytosterol esters. The non-sterol solubilizer may include one or more hydrophobic surfactants, one or more hydrophilic surfactants, and / or mixtures thereof.

[0072] Lipophilic or hydrophobic surfactants as defined herein are poorly water soluble or water insoluble and have a hydrophilic-lipophilic balance (HLB) value of less than 10, preferably less than 5, and more preferably an HLB of 1 to 3. HLB is an empirical expression of the relationship of the hydrophilic and hydrophobic groups of a surface-active amphiphilic molecule such as a surfactant. It is used to index surfactants, and its value varies from about 1 to about 45, including both non-ionic and ionic surfactants. It is well known that the higher the HLB, the more water-soluble / dispersible the surfactant is.

[0073] Exemplary lipophilic surfactants include, but are not limited to, Maisine 35-1, Imwitor 742, Capmul MCM, Capmul PG 12, Lauroglycol 90, Lauroglycol FCC, Caproyl 90, Captex 250, fatty acids selected from the group consisting of octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid. Fatty acids may contain both lipophilic and hydrophilic components and therefore may be characterized as either lipophilic or hydrophilic surfactants. As used herein, lipophilic surfactants may also be referred to as poorly water-soluble surfactants or hydrophobic surfactants.

[0074] Lipophilic surfactants suitable for use in the formulations described herein include, for example, fatty acids (C6 to C 24 , for example C 10 ~C 24 , for example C 14 ~C 24 ), such as octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid.

[0075] Suitable lipophilic surfactants for use in the formulations described herein include, for example, Imwitor 988 (glyceryl mono- / di-caprylate), Imwitor 742 (glyceryl mono- / di-caprylate / caprate), Imwitor 308 (glyceryl mono-caprylate), Imwitor 191 (glyceryl mono-stearate), Softigen 701 (glyceryl mono- / di-lysine oleate), Capmul MCM (glyceryl mono- / di-caprylate / caprate), Capmul MCM(L) (liquid form of Capmul MCM), Capmul GMO (glyceryl mono-oleate), Capmul GDL (glyceryl dilaurate), Maisine (glyceryl mono-linoleate), Peceol (glyceryl mono-oleate), Myverol 18-92 (monoglycerides distilled from sunflower oil) and Myverol 18-06 (monoglycerides distilled from hydrogenated soybean oil), Precirol ATO 5 (glyceryl palmitostearate) and Gelucire 39 / 01 (semi-synthetic glycerides, e.g. C 12~18 and mono- and / or di-glycerides of fatty acids such as mono-, di- and tri-glycerides.

[0076] Suitable lipophilic surfactants for use in the formulations described herein include, for example, acetate, succinate, lactate, citrate and / or tartarate esters of mono- and / or di-glycerides of fatty acids, such as Myvacet 9-45 (distilled acetylated monoglyceride), Miglyol 829 (caprylic / capric diglyceryl succinate), Myverol SMG (mono / di-succinylated monoglyceride), Imwitor 370 (glyceryl stearate citrate), Imwitor 375 (glyceryl monostearate / citrate / lactate) and Crodatem T22 (diacetyl tartaric acid esters of monoglycerides).

[0077] Lipophilic surfactants suitable for use in the formulations described herein include, for example, propylene glycol mono- and / or di-esters of fatty acids, such as Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene glycol monomyristate), Captex 200 (propylene glycol dicaprylate / dicaprate), Miglyol 840 (propylene glycol dicaprylate / dicaprate) and Neobee M-20 (propylene glycol dicaprylate / dicaprate).

[0078] Lipophilic surfactants suitable for use in the formulations described herein include, for example, polyglycerol esters of fatty acids such as Plurol oleique (polyglyceryl oleate), Caprol ET (polyglyceryl mixed fatty acids) and Drewpol 10.10.10 (polyglyceryl oleate).

[0079] Lipophilic surfactants suitable for use in the formulations described herein include, for example, castor oil ethoxylates with low ethoxylate content (HLB<10), such as Etocas 5 (5 moles of ethylene oxide are reacted with 1 mole of castor oil) and Sandoxylate 5 (5 moles of ethylene oxide are reacted with 1 mole of castor oil).

[0080] Lipophilic surfactants suitable for use in the formulations described herein include, for example, acid and ester ethoxylates formed by reacting fatty acids or glycerol esters of fatty acids (HLB<10) with ethylene oxide, such as Crodet 04 (polyoxyethylene(4) laurate), Cithrol 2MS (polyoxyethylene(2) stearate), Marlosol 183 (polyoxyethylene(3) stearate) and Marlowet G12DO (glyceryl 12EO dioleate).

[0081] Lipophilic surfactants suitable for use in the formulations described herein include, for example, sorbitan esters of fatty acids, such as Span 20 (sorbitan monolaurate), Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitan monooleate).

[0082] Lipophilic surfactants suitable for use in the formulations described herein include, for example, transesterification products of natural or hydrogenated vegetable oil triglycerides and polyalkylene polyols (HLB<10), such as Labrafil M1944CS (polyoxyethylated apricot kernel oil), Labrafil M2125CS (polyoxyethylated corn oil), and Gelucire 37 / 06 (polyoxyethylated hydrogenated coconut).

[0083] Lipophilic surfactants suitable for use in the formulations described herein include, for example, alcohol ethoxylates (HLB<10), such as Volpo N3 (polyoxyethylenated (3) oleyl ether), Brij 93 (polyoxyethylenated (2) oleyl ether) and Marlowet LA4 (polyoxyethylenated (4) lauryl ether).

[0084] Lipophilic surfactants suitable for use in the formulations described herein include, for example, Pluronics, such as polyoxyethylene-polyoxypropylene copolymers and block copolymers (HLB<10), such as Synperonic PE L42 (HLB=8) and Synperonic PE L61 (HLB=3).

[0085] In some embodiments, mixtures of lipophilic surfactants, for example as described above, may be used in the formulations described herein.

[0086] Formulations suitable for use in the methods described herein include any pharma- ceutically acceptable hydrophilic surfactant (e.g., having an HLB value greater than 10). Some non-limiting examples include castor oil or hydrogenated castor oil ethoxylates (HLB>10), such as Cremophor EL (polyoxyethylene (35) castor oil), Cremophor RH40 (polyoxyethylene (40) hydrogenated castor oil), Etocas 40 (polyoxyethylene (40) castor oil), Nikkol HCO-60 (polyoxyethylene (60) hydrogenated castor oil), Solutol HS-15 (polyethylene glycol 660 hydroxystearate), Labrasol (caprylocaproyl macrogol-8 glyceride), α-tocopherol-polyethylene glycol-1000-succinate (TPGS), and ascorbyl-6 palmitate.

[0087] Hydrophilic surfactants suitable for use in the formulations described herein include, for example, polyoxyethylene sorbitan fatty acid derivatives, such as Tween 20 (polyoxyethylene (20) monolaurate), Tween 80 (polyoxyethylene (20) monooleate), Crillet 4 (polyoxyethylene (20) monooleate), and Montanox 40 (polyoxyethylene (20) monopalmitate).

[0088] Suitable hydrophilic surfactants for use in the formulations described herein include, for example, gelucire, preferably Gelucire 50 / 13 (PEG mono- and diesters of palmitic and stearic acid). (For Gelucire, the first number (e.g., 50) corresponds to the melting point of the material and the second number (e.g., 13) corresponds to the HLB number.)

[0089] Suitable hydrophilic surfactants for use in the formulations described herein include, for example, fatty acid ethoxylates (HLB>10), such as Myrj 45 (polyoxyethylene (8) stearate), Tagat L (polyoxyethylene (30) monolaurate), Marlosol 1820 (polyoxyethylene (20) stearate) and Marlosol OL15 (polyoxyethylene (15) oleate). Myrj 45 is preferred.

[0090] Suitable hydrophilic surfactants for use in the formulations described herein include, for example, alcohol ethoxylates (HLB>10), such as Brij 96 (polyoxyethylene (10) oleyl ether), Volpo 015 (polyoxyethylene (15) oleyl ether), Marlowet OA30 (polyoxyethylene (30) oleyl ether), and Marlowet LMA20 (polyoxyethylene (20) C 12 ~C 14 fatty ethers).

[0091] Hydrophilic surfactants suitable for use in the formulations described herein include, for example, polyoxyethylene-polyoxypropylene copolymers and block copolymers (HLB>10), which are commercially available under the trade names Pluronic or Poloxamer, such as Poloxamer 188 and 407, also known as Syperonic PE L44 (HLB=16) and Syperonic F127 (HLB=22), respectively.

[0092] Hydrophilic surfactants suitable for use in the formulations described herein include, for example, anionic surfactants, such as sodium lauryl sulfate, sodium oleate, and dioctyl sodium sulfosuccinate.

[0093] Hydrophilic surfactants suitable for use in the formulations described herein include, for example, alkylphenol surfactants (HLB>10), such as Triton N-101 (polyoxyethylene (9-10) nonylphenol) and Synperonic NP9 (polyoxyethylene (9) nonylphenol).

[0094] In some embodiments, mixtures of hydrophilic surfactants, for example, as described above, may be used in the formulations described herein.

[0095] In some embodiments, mixtures of hydrophilic and lipophilic surfactants, for example as described above, may be used in the formulations described herein.

[0096] The formulations described herein may also include one or more additional co-solvents. Suitable co-solvents for use with the formulations described herein include short chain mono-, di-, and polyhydric alcohols, such as, for example, ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, polyethylene glycols having an average molecular weight of about 200 to about 10,000, diethylene glycol monoethyl ether (e.g., Transcutol HP), and combinations thereof. In some embodiments, the formulation further comprises water.

[0097] The formulations described herein may include additional oils. Additional oils that may be incorporated in embodiments of the invention include low molecular weight (up to C6) mono-, di-, or polyhydric alcohols and medium chain (C7-C 13 ) or long chain (C 14 ~C 22) fatty acid complete glycerol triesters.Thus, some examples of oils for use in the present invention include vegetable oils (e.g., soybean oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond, borage, peppermint and apricot kernel oil) and animal oils (e.g., fish liver oil, shark oil and mink oil).

[0098] In some preferred embodiments, formulations suitable for use in the methods described herein include a TU, a non-sterol solubilizer, and a phytosterol or phytosterol ester or mixtures thereof. For example, a formulation may include about 5% to about 40% by weight of a TU, about 10% to about 90% by weight of a non-sterol solubilizer, and about 2% to about 45% by weight of a phytosterol or phytosterol ester. For example, the formulation may contain TU at about 5% to about 40% by weight of the formulation (e.g., about 5% to about 35% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, about 10% to about 35% by weight, about 10% to about 25% by weight, about 10% to about 20% by weight, about 10% to about 15% by weight, about 15% to about 35% by weight, about 15% to about 30% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight). The formulation may be about 10% by weight to about 90% by weight (e.g., about 10% by weight to about 80% by weight, about 10% by weight to about 70% by weight, about 10% by weight to about 60% by weight, about 10% by weight to about 50% by weight, about 10% by weight to about 40% by weight, about 10% by weight to about 30% by weight, about 10% by weight to about 20% by weight, about 20% by weight to about 90% by weight, about 20% by weight to about 80% by weight, about 20% by weight to about 70% by weight, about 20% by weight to about 60% by weight, about 20% by weight to about 50% by weight, about 20% by weight to about 40% by weight, about 20% by weight to about 30% by weight, about 30% by weight to about 90% by weight, about 30% by weight to about 80% by weight, about 30% by weight to about 70% by weight, about 30% by weight to about 30% by weight, % to about 60% by weight, about 30% to about 50% by weight, about 30% to about 40% by weight, about 40% to about 90% by weight, about 40% to about 80% by weight, about 40% to about 70% by weight, about 40% to about 60% by weight, about 40% to about 50% by weight, about 50% to about 90% by weight, about 50% to about 80% by weight, about 50% to about 70% by weight, about 50% to about 60% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, about 60% to about 70% by weight, about 70% to about 90% by weight, about 70% to about 80% by weight, or about 80% to about 90% by weight.In some embodiments, the formulation may contain about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight of a non-sterol solubilizer. The formulation may contain about 2% to about 45% by weight of a phytosterol or phytosterol ester or mixture thereof. For example, the formulation may contain about 5% to about 35%, about 5% to about 25%, about 5% to about 20%, about 10% to about 35%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, about 15% to about 35%, about 15% to about 30%, about 15% to about 25%, or about 15% to about 20% by weight of phytosterol or phytosterol ester. In some embodiments, the formulation contains about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% by weight of phytosterol or phytosterol ester or mixtures thereof. The phytosterols may be selected from β-sitosterol, campesterol, stigmasterol, stigmastanol, campestanol, brassicasterol, ergosterol, lupeol and cycloartenol, and likewise the phytosterol esters may be fatty acid esters of phytosterols selected from β-sitosterol, campesterol, stigmasterol, stigmastanol, campestanol, brassicasterol, ergosterol, lupeol and cycloartenol.

[0099] In some embodiments, the formulation comprises about 10% to about 25% by weight (e.g., about 15% to about 25% by weight, e.g., about 18.2% by weight) of solubilized testosterone undecanoate; about 5 to about 40% by weight (e.g., about 5% to about 30% by weight, about 10% to about 20% by weight, e.g., about 15.0% by weight) of a hydrophilic surfactant; about 15% to about 65% by weight (e.g., about 20% to about 60% by weight, about 30% to about 50% by weight, e.g., about 39.9% by weight) of a hydrophobic surfactant; about 2% to about 45% by weight (e.g., about 5% to about 40% by weight, about 10% to about 30% by weight, e.g., about 25.0% by weight) of a phytosterol ester; and about 0 to about 15% by weight (e.g., about 0 to about 10% by weight, e.g., about 0 to about 5% by weight, e.g., about 2.0% by weight) of a solubilizing agent.

[0100] In some embodiments, the hydrophilic surfactant is polyoxyl 40 hydrogenated castor oil (e.g., Cremophor RH40). In some embodiments, the hydrophilic surfactant is propylene glycol monolaurate (e.g., Lauroglycol 90). In some embodiments, the solubilizing agent is dl-alpha tocopherol (e.g., vitamin E) and / or its esters or acetates. In some embodiments, the formulation comprises about 18.2% by weight solubilized testosterone undecanoate; about 15.0% by weight polyoxyl 40 hydrogenated castor oil; about 39.9% by weight propylene glycol monolaurate; about 25.0% by weight one or more phytosterol esters; and about 2.0% by weight dl-alpha-tocopherol and / or its esters or acetates.

[0101] Dose setting The method described herein includes adjusting the dosage of TU to optimize one or more PK parameters. The method includes administering to a subject a pharmaceutical composition comprising testosterone undecanoate (TU), a non-sterol solubilizer effective for solubilizing TU, and a phytosterol or phytosterol ester. The subject has not previously been administered TU or other testosterone replacement therapy (e.g., a prodrug of TU) for a period of at least 7 days (e.g., 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year or more). For example, the period can be sufficient to flush all exogenous testosterone from the body.

[0102] The initial dose of TU can be about 100 mg to about 1000 mg of TU (e.g., about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000). In some embodiments, the initial dose is about 400 mg. This can be administered daily until a first steady-state serum concentration of testosterone is reached. The method can include providing a first serum value of testosterone in the subject after administration of the TU. In addition, the method can further include, for example, performing a first titration of testosterone undecanoate as needed. If the first serum level of testosterone is less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration of about 400 ng / dL), the dosage can be increased, for example, by about 25%, 50%, 100%, 150%, 200% or more. For example, if the initial dosage is about 400 mg, the dosage can be increased, for example, to about 600 mg TU. This can establish a second steady-state serum level of testosterone that is higher than the first serum level of testosterone. When the first serum level of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), the dosage can be maintained at, for example, about 400 mg. This allows the first steady-state serum level of testosterone to be maintained. If the first serum level of testosterone is greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration greater than about 900 ng / dL), the dosage may be decreased, for example, by about 25%, 50%, 100%, 150%, 200% or more. For example, if the initial dosage is about 400 mg, the dosage may be decreased, for example, to about 200 mg TU. This may establish a second steady-state serum level of testosterone that is lower than the first serum level of testosterone (see FIG. 6).

[0103] When titration is performed, the dosage of TU may be increased, decreased or maintained. The dosage may be increased by about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. The dosage may be decreased by about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

[0104] Serum or plasma concentration measurements can be performed at any time after the initiation of TU treatment. For example, serum or plasma concentrations can be measured 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more after the initiation of TU administration during a treatment regimen.

[0105] Titration can be performed at any time after the initial administration of TU in a treatment regimen. Titration can be in response to serum or plasma concentration measurements made after the initial administration of TU in a treatment regimen. For example, titration can be performed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more after serum or plasma concentration measurements. In some embodiments, titration can be performed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more after the initial administration of TU in a treatment regimen.

[0106] Serum levels of testosterone may be measured after administration of TU. For example, plasma or serum T concentrations may be measured about 3 hours to about 5 hours (e.g., 3 hours, 4 hours, or 5 hours) after administration. Plasma or serum T concentrations may be measured after morning administration. In some embodiments, plasma or serum T concentrations may be measured about 3 hours to about 6 hours after administration. The pharmaceutical composition may be administered with a meal. Alternatively, the pharmaceutical composition may be administered without a meal. The pharmaceutical composition may be administered in two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses. The pharmaceutical composition may be administered in two doses per day (e.g., twice daily administration). A first dose may be administered in the morning, and a second dose may be administered in the evening. The doses may be equal. Alternatively, the doses may be different. For example, when a daily dose of about 400 mg TU is administered, the first dose may contain about 200 mg TU and the second dose may contain about 200 mg TU.

[0107] In some embodiments, after the first titration, the dosage may be increased to about 600 mg TU, with the first dose containing about 300 mg TU and the second dose containing about 300 mg TU; the dosage may be maintained at about 400 mg TU, with the first dose containing about 200 mg TU and the second dose containing about 200 mg TU; or the dosage may be decreased to about 200 mg TU, with the first dose containing about 100 mg TU and the second dose containing about 100 mg TU.

[0108] In some embodiments, the method further comprises providing a second serum level of testosterone.

[0109] In some embodiments, the method further includes performing a second titration, for example, after a second serum level of testosterone measurement.

[0110] After the first titration, about 600 mg of TU can be administered to the subject daily. If the second serum level of testosterone is less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration of less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration of less than about 400 ng / dL), the method can include orally administering about 800 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is higher than the second steady-state serum level of testosterone. If the second serum level of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), the method can include continuing to orally administer about 600 mg of TU to the subject daily to maintain the second steady state serum level of testosterone. If the second serum value of testosterone is greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration greater than about 900 ng / dL), the method can include orally administering about 400 mg of TU to the subject daily to establish a third steady-state serum value of testosterone that is lower than the second steady-state serum value of testosterone.

[0111] After the first titration, about 400 mg of TU can be administered to the subject daily. If the second serum level of testosterone is less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration less than about 400 ng / dL), the method can include orally administering about 600 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is higher than the second steady-state serum level of testosterone. If the second serum level of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), the method can include continuing to orally administer about 400 mg of TU to the subject daily to maintain the second steady state serum level of testosterone. If the second serum value of testosterone is greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration greater than about 900 ng / dL), the method can include orally administering about 200 mg of TU to the subject daily to establish a third steady-state serum value of testosterone that is lower than the second steady-state serum value of testosterone.

[0112] After the first titration, about 200 mg of TU can be administered to the subject daily. If the second serum level of testosterone is less than about 400 / F ng / dL or less than 400 / F+b ng / dL (e.g., a serum concentration of less than about 449 ng / dL or less than about 460 ng / dL or a plasma concentration of less than about 400 ng / dL), the method can include orally administering about 400 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is higher than the second steady-state serum level of testosterone. If the second serum level of testosterone is about 400 / F ng / dL to about 900 / F ng / dL or about 400 / F+b ng / dL to about 900 / F+b ng / dL (e.g., a serum concentration of about 449 ng / dL to about 1011 ng / dL or about 460 ng / dL to about 971 ng / dL or a plasma concentration of about 400 ng / dL to about 900 ng / dL), the method can include continuing to orally administer about 200 mg of TU to the subject daily to maintain the second steady state serum level of testosterone. If the second serum level of testosterone is greater than about 900 / F ng / dL or greater than 900 / F+b ng / dL (e.g., a serum concentration greater than about 1011 ng / dL or greater than about 971 ng / dL or a plasma concentration greater than about 900 ng / dL), the method can include orally administering about 100 mg of TU to the subject daily to establish a third steady-state serum level of testosterone that is lower than the second steady-state serum level of testosterone.

[0113] In some embodiments, after the second titration, the dosage may be increased to about 800 mg TU, with the first dose containing about 400 mg TU and the second dose containing about 400 mg TU; or the dosage may be decreased to about 100 mg TU, with the subject receiving a single dose of about 100 mg TU. The single dose of about 100 mg TU may be administered in the morning or evening.

[0114] The first serum level of testosterone can be measured after reaching a steady state. For example, the first serum level of testosterone can be measured on day 1 of the treatment regimen, e.g., from about day 1 to about day 21, e.g., from about day 7 to about day 21 (e.g., day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, e.g., day 14).

[0115] The first titration can be performed any time after the first serum level of testosterone is measured, for example, from about day 1 to about day 35, for example, from about day 7 to about day 35, for example, from about day 21 to about day 35 (e.g., day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35, for example, day 28) of the treatment regimen. The first titration may be performed on about day 30 to about day 60 (e.g., day 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60) of the treatment regimen.

[0116] For example, the first serum level of testosterone may be measured on about day 14 of the treatment regimen, and / or the first titration may be performed on about day 28 of the treatment regimen.

[0117] The second serum value of testosterone may be measured after the first titration, e.g., after the second steady-state serum value is reached. For example, the second serum value of testosterone may be measured at about day 35 to about day 49 of the treatment regimen (e.g., day 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, e.g., day 42). The second titration may be performed, for example, after the second serum value of testosterone measurement. The second titration may be performed at about day 49 to about day 63 of the treatment regimen (e.g., day 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63, e.g., day 56). For example, a second serum level of testosterone can be measured at about day 42 and a second dose titration can be made at about day 56.

[0118] In some embodiments, the first titration may be performed on about day 28 of the treatment regimen, and / or the second titration may be performed on about day 56 of the treatment regimen.

[0119] In some embodiments, the first titration may be performed, for example, on about day 21 to about day 35 (e.g., day 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, e.g., day 28) of the treatment regimen. After the first titration, a second steady-state serum value of testosterone may be established. A second serum value of testosterone may then be measured. A second titration may then be performed.

[0120] In some embodiments, the method reduces the risk of elevated blood pressure. For example, in some embodiments, the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure do not increase by more than about 5 mmHg compared to baseline (e.g., not more than about 4, 3, or 2 mmHg). In some embodiments, the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure do not increase by more than about 3 mmHg compared to baseline. In some embodiments, the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure do not increase by more than about 2 mmHg compared to baseline when measured by ambulatory blood pressure monitoring (ABPM). In some embodiments, the subject is diabetic or hypertensive, and the daytime systolic blood pressure, the nighttime systolic blood pressure, and / or the 24-hour average systolic blood pressure do not increase by more than about 4 mmHg compared to baseline when measured by ambulatory blood pressure monitoring (ABPM). In some embodiments, the first serum value and / or the second serum value are measured by measuring the testosterone concentration of serum that has been clotted prior to centrifugation in tubes (e.g., for about 30 to about 50 minutes, e.g., at room temperature), measuring the testosterone concentration of plasma in tubes supplemented with EDTA and NaF, and multiplying the testosterone concentration by the reciprocal of a predefined coefficient F (1 / F) or an equivalent method such as an immunoassay. In some embodiments, K2 / EDTA tubes or other plasma tubes may be used.

[0121] In some embodiments, the method includes performing a treatment regimen that includes administering to the subject a pharmaceutical composition that includes testosterone undecanoate (TU), a non-sterol solubilizer effective to solubilize the TU, and a phytosterol or phytosterol ester. About 400 mg of TU can be administered, for example, at the beginning of the treatment regimen. The method can include establishing a first steady-state serum concentration of testosterone. The method can include providing a first serum value of testosterone in the subject after administration of the TU. In addition, the method can further include, for example, performing a first titration of testosterone undecanoate as needed. If the first serum value of testosterone is less than about 460 ng / dL, the daily dosage can be increased, for example, to about 600 mg of TU. This can establish a second steady-state serum value of testosterone that is higher than the first steady-state serum value of testosterone. If the first serum value of testosterone is between 460 ng / dL and about 971 ng / dL, the daily dosage can be maintained. This can maintain the first steady-state serum value of testosterone. If the first serum value of testosterone is greater than about 971 ng / dL, the daily dosage can be increased, for example, to about 200 mg TU. This can establish a second steady-state serum value of testosterone that is lower than the first steady-state serum value of testosterone. The subject can be, for example, on antihypertensive therapy and can show a mean change in systolic blood pressure of 3.4 mmHg or less, a mean change in diastolic blood pressure of 1.8 mmHg or less, and / or a mean change in heart rate of 1.3 beats per minute or less. The subject can have diabetes mellitus and can show a mean change in systolic blood pressure of 3.0 mmHg or less, a mean change in diastolic blood pressure of 1.7 mmHg or less, and / or a mean change in heart rate of 1.9 beats per minute or less.

[0122] The above-mentioned titration scheme may be more advantageous than other titration schemes. For example, a starting dose of about 400 mg of TU may be more advantageous than other starting doses of TU, ​​such as 800 mg, 700 mg, 600 mg, 500 mg, 300 mg, 200 mg, or 100 mg. A starting dose of about 400 mg of TU may be more advantageous than a starting dose of about 600 mg of TU. A starting dose of about 400 mg of TU may be more advantageous than a starting dose of about 200 mg of TU. Additionally, providing serum levels of testosterone on about day 1 to about day 21 (e.g., day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, e.g., day 14) and / or on about day 35 to about day 49 (e.g., day 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, e.g., day 42) of a treatment regimen may be advantageous over providing serum levels of testosterone on days outside of these ranges or during certain days. Performing titration on about day 1 to about day 35 (e.g., day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35, e.g., day 28) and / or on about day 49 to about day 63 (e.g., day 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 63, e.g., day 56) of a treatment regimen may be advantageous over performing titration on days outside these ranges or during certain days. Furthermore, dose setting decisions may be made using a NaF / EDTA plasma Cavg concentration range of about 400 ng / dL to about 900 mg / dL or a serum Cavg concentration range of about 449 ng / dL to about 1011 ng / dL (e.g., when F is 0.89) or about 460 ng / dL to about 971 ng / dL (e.g., when the slope 1 / F is 1.023 and b is 50.45), which may result in more favorable results compared to a Cavg concentration range of about 300 ng / dL to about 1000 ng / dL.Advantageous properties of using the starting dose, Cavg boundaries and days to measure serum or plasma concentrations of testosterone and / or perform titration of TU doses as described herein include increasing accurate titration determinations, decreasing inaccurate titration determinations, reducing the risk of titration, obtaining a population of subjects with more subjects within the desired FDA guidelines (e.g., serum Cavg in the normal range of 300-1000 ng / dL in 75% of subjects, Cmax less than 1500 ng / dL in 85% of subjects, 5% or less of 1800-2500 ng / dL and not exceeding 2500 ng / dL), improving patient compliance, reducing blood pressure, reducing the risk of elevated blood pressure, and increasing responsiveness to testosterone replacement therapy to treat testosterone deficiency in subjects in need thereof.

[0123] In some embodiments, the population mean has a Cmax / Cavg ratio from 0 to 24 hours of less than 2.5; a Cmax / Cavg ratio from 0 to 12 hours of less than 2.2; and / or a Cmax / Cavg ratio from 12 to 24 hours of less than 2.2. EXAMPLES

[0124] Working Example Example 1. High dose titration scheme Study drug doses were titrated during the efficacy period using an algorithm developed using 24-hour PK data from an 84-day Phase 2b study of SOV2012-F1 in 36 subjects. The final dose established in the 90-day efficacy period for SOV2012-F1 was used at the start of the 9-month safety evaluation period, and the dose was escalated or de-escalated on days 180 and 270 based on plasma T concentrations from single blood draws (days 166 and 256) within 3-5 hours of dosing. Subjects receiving AndroGel were escalated or de-escalated on days 180 and 270 based on serum T C predose levels from single blood draws on days 166 and 256, according to the product information.

[0125] Dose reductions were made for safety based on nominal hemoglobin levels of >18 g / dL measured on days 90, 180, and 270 during the study.

[0126] SOV2012-F1 group Titration for each subject (starting dose was 400 mg TU am and 200 mg TU pm) was based on plasma T measured 3-5 hours (+10 min) after the morning dose on days 14 and 42. Titration, as needed, was performed on days 28 and 56 based on the following algorithm: For subjects who may require dose titration on Day 28 based on plasma T levels obtained at 3-5 hours on Day 14: T3-5 < 235ng / dL: Dose increased to 800mg (400mg am, 400mg pm) ○T3-5≧235~≦1120ng / dL: No change in dosage ○T3-5>1120ng / dL: Dose reduced to 400mg (200mg am, 200mg pm) For subjects who may require dose titration on Day 56 based on plasma T levels obtained at 3-5 hours on Day 42: For subjects whose dose was not previously titrated (e.g., remained at 400 mg am, 200 mg pm) and whose plasma T3-5 obtained on Day 42 is: T3-5<235ng / dL: Dose increased to 800mg (400mg am, 400mg pm) T3-5≧235~≦1120ng / dL: No change in dosage T3-5>1120ng / dL: Dose reduced to 400mg (200mg am, 200mg pm) For subjects whose dose was previously reduced to 400 mg (200 mg am, 200 mg pm) and whose plasma T3-5 obtained on Day 42 is: T3-5<235ng / dL: dose increased to 600mg (400mg am, 200mg pm) T3-5≧235~≦1120ng / dL: No change in dosage T3-5>1120ng / dL: The dose may be further reduced to 200mg am For subjects whose dose has not been previously increased to 800 mg (400 mg am, 400 mg pm) and whose plasma T3-5 obtained on Day 42 is: T3-5<235ng / dL: The investigator and sponsor will review the data for each individual and the reasons for not responding to treatment will be further investigated. Assuming good compliance with the study drug, the dose may be increased to 1000mg (600mg am, 400mg pm) at the investigator's discretion while taking into account safety, or the subject may be discontinued from the study as a non-responder. T3-5≧235~≦1120ng / dL: No change in dosage T3-5>1120ng / dL: Dose reduced to 600mg (400mg am, 200mg pm)

[0127] If analysis of the 24-hour PK data on Day 90 reveals that a subject is receiving an incorrect dose, discontinuation of the subject may be appropriate.

[0128] During the 9-month safety evaluation period, doses were escalated or de-escalated on days 180 and 270 using single-timepoint T measurements obtained 3-5 hours after the morning dose on days 166 and 256, respectively. A schematic of SOV2012-F1 dose selection in this study is provided in Figure 1.

[0129] method: We utilized a similar algorithm from the clinical pharmacology review of the Axiron product to derive a single blood draw scheme based on data from our Phase IIb study.

[0130] Briefly, we performed a comparison between dosing recommendations made based on total plasma T concentrations (Cx) from a single blood draw and dosing recommendations made based on 24-hour T Cavg or Cmax.

[0131] Figure 2 depicts theoretical results (determination of accurate or inaccurate dosing) using a single blood draw at various time points including 0, 1.5, 3, 4, 5, 6, 8, 10 or 12 hours after the AM dose to predict 24 hour T compared to the calculated 24 hour T. To demonstrate the approach, this figure uses the commonly accepted serum normal T range of 300-1000 ng / dL.

[0132] Ranges with discrepancies between Cx-based dosing recommendations and 24-h T Cavg-based dosing recommendations are defined as "inaccurate" (e.g., ranges I-VI), whereas ranges where both dosing recommendations agree are defined as "accurate" (e.g., ranges A, B, and C).

[0133] The percentage of subjects within ranges A, B, and C represent accurate titration determinations made from single blood draw plasma T levels, while the percentage of subjects within ranges I-VI represent inaccurate determinations, described as follows: I: Plasma T levels less than 300ng / dL but Cavg greater than 1000ng / dL II: Plasma T levels in the normal range, but Cavg >1000ng / dL III: Plasma T levels below 300 ng / dL, but Cavg in the normal range IV: Plasma T levels in the normal range, but Cavg < 300ng / dL V: Plasma T levels above 1000ng / dL, but Cavg in the normal range VI: Plasma T levels greater than 1000 ng / dL, but Cavg less than 300 ng / dL In the situations described in I, II, and III, dosing recommendations based on a single blood draw would result in a higher dose than necessary, while in the situations described in IV, V, and VI, dosing recommendations based on a single blood draw would result in a lower dose than necessary. The same framework applies to comparing Cmax vs. Cx.

[0134] result Decision based on Cavg Based on a comparison of 24 hour T Cavg-based or Cmax-based dosing decisions from days 7+14 of the combined Phase 2b studies (400 mg am / 400 mg pm regimen only), we found that 0, 1.5, 10 and 12 hours were not suitable for making dosing decisions, while 3 to 8 hours after the morning dose appeared to be an appropriate range for a single blood draw.

[0135] Figure 3 suggests that dosing based on a single blood draw 3 to 8 hours after the morning dose provided the best agreement with dosing recommendations based on 24-hour T Cavg (72 to 86% accurate dosing decisions).

[0136] Table 1 summarizes the presence of each unnecessary dose setting.

[0137] [Table 1]

[0138] Figure 4 shows the percentage of incorrect titration decisions based on a single blood draw that results in a higher or lower dose than necessary. As Figure 4 suggests, it is reasonable to suggest that subjects should be titrated based on a blood draw obtained 3-8 hours after the morning administration of drug.

[0139] Decision based on Cmax combined with Cavg We also compared Cmax-based decisions regarding the impact of different thresholds for dose tapering decisions. Incorporating Cmax into the dose-setting algorithm addresses the safety risk of T levels above 1500 ng / dL.

[0140] Figure 5 suggests that titration based on a single blood draw 3-5 hours after the morning dose results in the best agreement (91.7%-100%) with the recommendation of titration based on Cmax 0-12 using thresholds of 235 and 1400 ng / dL. T values ​​(Cx) below the lower limit of 235 ng / dL result in dose escalation to achieve Cavg within the normal range. T values ​​(Cx) above the upper limit of 1400 ng / dL result in dose de-escalation to maintain Cmax values ​​below 1500 ng / dL. Application of the range 300-1000 ng / dL resulted in a lower percentage of accurate titration. In addition, 8 hours after the morning dose resulted in a lower percentage of accurate titration determinations and is therefore not recommended. Six hours after the morning dose, we observed five subjects in the Phase 2b study who had a Cmax >1600 ng / dL but did not meet the decision for dose tapering based on plasma T levels. Therefore, we propose to use a 3-5 hour time frame for our Phase 3 study.

[0141] [Table 2]

[0142] Table 2 confirms that 6 and 8 hours were not appropriate for single blood draws and that the range of 235-1400 ng / dL yielded lower inaccuracy percentages for both cases.

[0143] A single blood sampling window of 3-5 hours after the morning dose was proposed. Dose escalation and de-escalation thresholds were set at 235 ng / dL and 1400 ng / dL, respectively, to minimize the percentage of inaccurate determinations while achieving a high percentage of accurate determinations.

[0144] Both Day 49 and Day 84 in the Phase IIb study have 24-hour PK data. We evaluated data on these 2 days for 15 subjects who received the 400mg AM / 200mg PM dosing regimen, which was the starting dose in the Phase 3 study. The proposed titration window of a single blood draw of 3-5 hours and a threshold of 235-1400ng / dL were validated by this approach.

[0145] Dosing Scheme In conclusion, we suggest that a single blood draw used for dose titration determination be obtained 3-5 hours after the morning dose. Subjects with a single blood draw of total plasma T below 235 ng / dL were dose escalated. Subjects with a single blood draw of total plasma T above 1120 ng / dL were dose de-escalated.

[0146] Example 2. Adjustment of a new dosing titration scheme Number of targets Up to approximately 170 completed subjects consented to the Study 1 EXT study and received treatment with SOV2012-F1 for a total of 180 days after a minimum of 8 weeks off study medication or interim testosterone replacement therapy. Subjects were titrated to their final dose over the first 28-56 days of the treatment period. Study 1 EXT included 3-4 24-hour ABPM assessment sessions depending on when subjects entered the study (either directly from Study 1 or as subjects joining Study 1 EXT late or as newly enrolled Study 1 (naive subjects)).

[0147] Approximately 135 of the approximately 170 consented subjects (80%) were targeted to complete 120 days of the 180-day treatment period, including the required 24-h ABPM assessment sessions at baseline, Day 1, and Day 120 at 4 months in Study 1 EXT at a minimum.

[0148] Treatment during extension study, Study 1 EXT During the Study 1 EXT study period, all subjects were off their originally assigned Study 1 study medication or any interim testosterone replacement for 8 weeks. Upon completion of the washout, all subjects received SOV2012-F1 starting at a total daily dose of 400 mg (200 mg with breakfast and 200 mg with dinner), titrated as needed according to the titration algorithm established for the Study 1 EXT protocol. Dietary guidelines and dietary content were unchanged from the Study 1 protocol.

[0149] Continued test period Primary endpoint - Change from baseline in mean 24-hour ambulatory systolic blood pressure after approximately 120 days (± 3) of treatment. Determine response to lower starting doses of oral SOV2012-F1 with dose escalation and deescalation as appropriate, as measured by: Percentage of subjects treated with SOV2012-F1 with plasma T Cavg within the normal range after 90 days of treatment.

[0150] Secondary endpoints - Change from baseline in mean 24-hour ambulatory systolic blood pressure after approximately 180 days (± 3) of treatment. Change from baseline in hourly average ambulatory systolic blood pressure (daytime) from 7 AM to 10:30 PM after approximately 120 days (± 3) and 180 days (± 3) of treatment. Change from baseline in hourly average ambulatory systolic blood pressure (nighttime) from 11 PM to 6:30 AM after approximately 120 days (± 3) and 180 days (± 3) of treatment. Maximum 24-hour systolic blood pressure after approximately 120 days (±3) and 180 days (±3) of treatment. Change from baseline in hourly average ambulatory diastolic blood pressure (daytime) from 7 AM to 10:30 PM after approximately 120 days (± 3) and 180 days (± 3) of treatment. Change from baseline in hourly average ambulatory diastolic blood pressure (nocturnal) from 11 PM to 6:30 AM after approximately 120 days (± 3) and 180 days (± 3) of treatment. · Change from baseline in 24-hour mean diastolic blood pressure (dBP) measured by ABPM after 120 days (± 3) and 180 days (± 3) of treatment in subjects treated with SOV2012-F1. Maximum 24-hour diastolic blood pressure after approximately 120 days (±3) and 180 days (±3) of treatment. Change from baseline in 24-hour mean ambulatory heart rate after approximately 120 days (±3) and 180 days (±3) of treatment. Change from baseline in hourly average ambulatory heart rate (daytime), 7 AM - 10:30 PM, after approximately 120 days (± 3) and 180 days (± 3) of treatment. Change from baseline in hourly average ambulatory heart rate (nighttime) from 11 PM to 6:30 AM after approximately 120 days (± 3) and 180 days (± 3) of treatment. Observations and changes from baseline in half-hour systolic blood pressure, diastolic blood pressure, and heart rate after approximately 120 days (±3) and 180 days (±3) of treatment. Percentage of subjects treated with SOV2012-F1 with maximum plasma testosterone concentration (TCmax) values ​​after 90 days of treatment: <1500 ng / dL; ○>1800~≦2500ng / dL; ○>2500ng / dL.

[0151] Safety evaluation items To determine the incidence of AEs, SAEs, and AEs leading to discontinuation of Study 1 EXT in subjects treated with SOV2012-F1. Observations and changes from baseline in BP and HR obtained in the clinic during the treatment period. Observations and changes from baseline in the following laboratory parameters in subjects treated with SOV2012-F1 during the treatment period: Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, alkaline phosphatase) Hematological parameters (hemoglobin) Hormone levels (luteinizing hormone [LH], follicle-stimulating hormone [FSH], DHT, sex hormone-binding globulin [SHBG] and thyroid-stimulating hormone [TSH]) Lipid profile (high-density lipoprotein, low-density lipoprotein, total cholesterol and triglycerides) ○Serum PSA

[0152] Dosing of SOV2012-F1 Study drug doses were titrated during the efficacy period using an algorithm developed using 90 days of 24-hour PK data from 133 Study 1 subjects in the SOV2012-F1 treatment arm. Dose titration for each subject was based on NaF / EDTA plasma T measured 3-5 hours (+10 minutes) after the morning dose on Days 14 and 42. Dose titration, as appropriate, occurred on Days 28 and 56 based on the following algorithm: For subjects who may require dose titration on Day 28 based on plasma T levels obtained at 3-5 hours on Day 14: T3-5 < 400ng / dL: Dose increased to 600mg (300mg AM, 300mg PM) ○T3-5≧400~≦900ng / dL: No change in dosage T3-5>900ng / dL: Dose reduced to 200mg (100mg AM, 100mg PM) For subjects who may require dose titration on Day 56 based on plasma T levels obtained at 3-5 hours on Day 42: For subjects whose dose was not previously titrated (e.g., remained at 200 mg AM, 200 mg PM) and whose plasma T3-5 obtained on Day 42 is: T3-5<400ng / dL: Dose increased to 600mg (300mg AM, 300mg PM) T3-5≧400~≦900ng / dL: No change in dosage T3-5>900ng / dL: Dose reduced to 200mg (100mg AM, 100mg PM) For subjects whose dose was previously reduced to 200 mg (100 mg AM, 100 mg pm) and whose plasma T3-5 obtained on Day 42 is: T3-5<400ng / dL: Dose increased to 400mg (200mg AM, 200mg PM) T3-5≧400~≦900ng / dL: No change in dosage T3-5>900ng / dL: Dose reduced to 100mg AM only For subjects whose dose was previously increased to 600 mg (300 mg AM, 300 mg PM) and whose plasma T3-5 obtained on Day 42 is: T3-5<400ng / dL: dose increased to 800mg (400mg AM, 400mg PM) T3-5≧400~≦900ng / dL: No change in dosage T3-5>900ng / dL: Dose reduced to 400mg (200mg AM, 200mg PM)

[0153] Measurement of T at 3–6 hours In Study 1 EXT, it was determined that measuring plasma T concentrations from about 3 hours to about 6 hours post-dose provided reliable plasma concentrations for phytosterol ester-containing formulations administered with a meal. T concentrations over the 0-6 hour post-dose period for visits on days 14 and 42 of Study 1 EXT. T measurements were made using plasma samples collected in NaF / EDTA tubes and analyzed by LC-MS / MS. Figure 7 shows low T levels from 0-2 hours post-dose and a relatively flat PK curve from 3-6 hours post-dose, indicating consistent plasma T values ​​over this time frame.

[0154] The ratio of plasma to serum results over the 3-6 hour time frame was also constant. If the ratio changed significantly over that time frame, the above titration thresholds would be time dependent. Table 3 below shows that the predefined coefficient F varies within a narrow range, thereby allowing dose adjustments based on samples obtained in the 3-6 hour time frame.

[0155] [Table 3]

[0156] Effectiveness (Cavg) The primary efficacy endpoint was the percentage of subjects treated with SOV2012-F1 with a 24-hour total T Cavg within the normal range after 90 days of treatment in the continuation.

[0157] Cavg was calculated by dividing the area under the concentration-time curve from 0 to 24 hours (AUC0-24) by the actual time between dosing and the 24-hour sample collection period.

[0158] Ambulatory systolic blood pressure (sBP) Change from baseline in 24-h mean sBP was analyzed as the primary blood pressure outcome. Key secondary analyses were derived from changes from baseline in daytime and nighttime sBP.

[0159] Least squares means and associated 90% CIs for differences were provided.

[0160] Ambulatory diastolic blood pressure (dBP) and ambulatory heart rate (HR) These were assessed in a similar manner to sBP, except for maximum heart rate. Hourly and half-hourly observed changes from baseline and time-matched changes were summarized descriptively.

[0161] Cmax The secondary endpoint was assessed by estimating the proportion of subjects treated with SOV2012-F1 at day 90 by T Cmax. a) Tcmax ≦ 1500ng / dL b) T Cmax>1800 and ≦2500ng / dL c) T Cmax>2500ng / dL

[0162] Dose titration decisions Exploratory analyses were performed using T concentrations obtained at titration time points from EDTA and serum tubes to compare predicted titration determinations with those made using NaF-EDTA samples. Table 4 shows the dose distribution of subjects from Study 1 and Study 1 EXT at Day 90.

[0163] [Table 4]

[0164] In summary, in Study 1 EXT, there were subjects who were initiated on 400 mg SOV2012-F1 daily and had plasma T measurements obtained in the 3-5 hour time frame after the morning dose and subjects who did not have dose adjustments to the titration thresholds of 400 and 900 ng / dl (plasma NAF / EDTA). These subjects had surprising results with both Cavg in the normal range, Cmax values ​​that met FDA criteria, and blood pressure results of less than 3.8 mm increase (e.g., less than 2 mm increase, less than 3 mm increase). Heart rate increase was also excellent (less increase vs. baseline).

[0165] In addition, we identified subjects who were initiated on 400 mg SOV2012-F1 daily and had plasma T measurements obtained in the time frame of 3-5 hours (or 3-6 hours) after the morning dose, and who had titration to plasma (NaF / EDTA) thresholds of 400 and 900 ng / dL (Figure 6). These subjects had surprising results with both Cavg in the normal range, Cmax values ​​that met FDA criteria, and blood pressure results of less than 4.9 mm increase (e.g., less than 2 mm increase, less than 3 mm increase). These blood pressure measurements were made by ABPM protocol. Heart rate increase was also excellent (less increase over baseline).

[0166] Example 3. Blood Pressure is Minimally Affected by This Titration Scheme Ambulatory blood pressure measurements were obtained for 134 subjects as described in Example 2 above. These data were compared directly with a TU formulation from Clarus Therapeutics that lacked phytosterol esters and was not subjected to the same dosing titration regimen described herein. Table 5 below shows the results.

[0167] [Table 5]

[0168] These data show that ABPM measurements for all patients increased by only 1.70 mmHg during the day, 1.65 mmHg overnight, and 1.64 mmHg in 24-hour average over baseline, compared with 5.0 mmHg, 4.9 mmHg, and 4.9 mmHg, respectively, for patients treated with the Clarus formulation.

[0169] Additionally, in-clinic systolic blood pressure and heart rate data for Study 1 and Study 1 EXT are provided below. As shown in Tables 6 and 7 below, Study 1 EXT resulted in a slower rise and lower maximum systolic blood pressure measurements than the Study 1 protocol. The mean change from baseline in heart rate from Days 90 to 180 for Study 1 EXT was 2.2 beats per minute (bpm), and the mean change for Study 1 (Days 90 and 180) was a change from baseline of 3.3 bpm.

[0170] [Table 6]

[0171] [Table 7]

[0172] Example 4. Effect of an oral TU formulation (SOV2012-F1) on ambulatory blood pressure in hypogonadal men method The study was an open-label, multicenter, single-arm study with a treatment-naive screening period at a baseline visit to assess BP and heart rate via 24-hour ambulatory BP monitoring (ABPM) prior to administration of study medication, and two visits at 120 and 180 days after initiation of oral testosterone undecanoate. In addition, seated clinic BP measurements were performed at all study visits. All study participants initially received oral testosterone undecanoate at a dose of 200 mg twice daily with breakfast and dinner. Dose reductions to 100 mg twice daily or increases to 300 mg twice daily were made on day 28 based on morning plasma testosterone thresholds (<400 ng / dL for dose escalation or >900 ng / dL for dose taper) 3-5 hours after the morning dose. Further potential titration of the dose (a minimum decrease of 100 mg daily or a maximum increase of 400 mg twice daily) was performed on day 56 to achieve therapeutic levels of plasma testosterone; the day 56 dose was maintained until the end of treatment (discontinuation or 180 days).

[0173] Study Participants All participants were males aged 18-65 years with documented hypogonadism as defined by subnormal serum testosterone and at least one sign or symptom of testosterone deficiency. Total serum testosterone levels were required to be ≦281 ng / dL for two blood samples obtained between 7:00 and 10:00 am on separate days, at least 3 days apart, in either individuals naive to androgen replacement or after at least 8 weeks off current androgen therapy (a maximum 6-month off period was required for testosterone implantation). No changes in medication, including antihypertensives, were also required within 3 months prior to enrollment, and a mean clinic BP of ≦140 systolic and ≦90 diastolic. Subjects with uncontrolled hypertension (clinic BP >140 / 90 mmHg) were excluded based on FDA guidance. The main exclusion criteria were the use of any medication or clinical condition that may affect testosterone undecanoate absorption or levels; hemoglobin A1c >8%; hemoglobin <11.0 g / dL or 16.0 g / dL; serum transaminases >2x upper limit of normal; estimated glomerular filtration rate <60 ml / min / 1.73 m or prostate specific antigen (PSA) >2.5 ng / ml and / or prostate abnormality by palpation. In addition, exclusion criteria attributable to ambulatory BP monitoring procedures were upper arm circumference >45 cm; long distance driving or planned outings of >60 min while wearing the monitor and cardiac arrhythmias (e.g., atrial fibrillation) that may interfere with the ability of the ambulatory BP recorder to obtain reliable measurements.

[0174] The study was performed in accordance with the requirements of Good Clinical Practice as stated in the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) guidelines and the current revision of the Declaration of Helsinki. The study protocol and informed consent form were reviewed and approved by the Copernicus Group Institutional Review Board (Cary, NC, USA). Written informed consent was obtained from each study participant before any study procedures were performed.

[0175] Safety assessment Clinical evaluations and vital signs were assessed at baseline and after 14, 42, 90, 119, and 179 days. At each clinic visit after the screening visit, all study participants were queried about adverse events and symptom-directed physical examinations were performed as clinically indicated. Laboratory tests were assessed at baseline and after 90 and 180 days.

[0176] Blood Pressure Monitoring Blood pressure was monitored manually in the clinic at baseline and at post-treatment study visits. Clinical measurements were made in triplicate in the sitting position using an appropriately sized cuff and bladder with a digital recorder after 10 min of rest. Any study participant with a baseline clinic mean BP >140 / 90 mmHg was withdrawn from the study. For ambulatory BP measurements, study participants were fitted with a recorder (Spacelabs Medical Model 90207; Redmond, WA) that was started to measure BP at 30-min intervals during the day (7:00 am-11:00 pm) and at night (11:00 pm-7:00 am). ABPM data were assessed for validity both manually and programmatically by a standardized, computerized method, requiring no more than 4 consecutive time points to be missing, no more than 10 of 48 possible time points over a 24-h period to be missing, and at least 22 time points during the 24-h period to have valid data. If these quality control criteria were not met, the test would be repeated within 48 hours of failure of the ambulatory BP procedure.

[0177] statistical analysis The mean 24-h, daytime and nighttime systolic and diastolic BP were summarised by means and 95% confidence intervals (CIs) and cumulative distribution curves. Direct comparisons of visits were performed using mixed model repeated measures (MMRM) analysis with study participants as random effects (all participants with no missing post-baseline outcomes) and visit, baseline diabetes status and baseline antihypertensive treatment status as fixed effects. Least squares means for each visit and the difference between 120 days and baseline with associated 95% CIs were calculated. Cumulative distribution function curves of the change from baseline to days 120 and 180 were also performed. The primary endpoint in this BP safety study was the change from baseline to day 120 in mean 24-h systolic BP. The key secondary endpoint was the change from baseline to day 180 in mean 24-h systolic BP. Comparisons were also made for ambulatory BP change at day 180 versus day 120. Other assessments included changes from baseline in awake (daytime) and sleep (nighttime) systolic BP, 24-hour, awake and sleep diastolic BP, and 24-hour, awake and sleep heart rate. In addition, changes in BP and heart rate were assessed in subgroups of study participants both with and without antihypertensive therapy at baseline and with and without a baseline history of diabetes mellitus. The incidence of adverse events was tabulated in all participants who received at least one dose of study drug (safety population).

[0178] The 24-hour BP change from baseline was calculated using the time-weighted average BP obtained over the 24 hours divided by the duration. The hourly average BP change was calculated by taking the difference between the corresponding hourly BP at the last day of treatment visit and the baseline visit for the first hour after a given dose. Post-hoc analyses were also performed to evaluate the associations between the changes from baseline in ambulatory systolic and diastolic BP and changes in weight, heart rate, testosterone concentrations, and hemoglobin.

[0179] Sample size calculation. A sample size of 135 subjects would yield a two-sided 90% confidence interval with a distance from the mean difference to the limit equal to 1.4 mmHg if the estimated standard deviation of the 120-day difference versus baseline in 24-hour mean systolic BP was 10 mmHg. In addition, a sample size of 119 study participants achieved 90% power to detect non-inferiority (vs. baseline) using a one-sided, one-sample t-test if the non-inferiority margin was 3.0 mmHg, the actual mean was 0, and the significance level (α) of the test was 0.025. Assuming a 10% dropout or non-evaluable ambulatory BP monitoring rate, 133 study participants would be required for enrollment to reach 119 evaluable study participants.

[0180] result Subject breakdown and baseline characteristics A total of 155 study participants were enrolled and received at least one dose of study medication. Of these 155 participants, 153 had evaluable ambulatory BP testing at baseline and 2 were discontinued from further participation in the study. 136 (89%) completed the 120-day visit and 125 (82%) completed the 180-day visit with valid baseline and successful on-treatment ABPM testing. The primary reasons for early termination were subject withdrawal (5.6%), adverse events (1.3%), loss to follow-up (6%), and other (2.6%). Demographic and baseline characteristics of study participants are shown in Table 8. The mean age at baseline was 51.2 years (52% were over 50 years), 77% were white, and 19% were black. Thirty-seven percent of study participants (56 of 155) were taking antihypertensive therapy. There were no dose escalations in antihypertensive medication, but five people (3.2%) started a new antihypertensive medication during the 180-day study. Twenty-two percent (34 of 155) of the study cohort had a history of diabetes mellitus. A higher percentage of study participants taking antihypertensive therapy had diabetes (44.6%) than those not taking antihypertensive therapy (9.1%). A higher percentage (96%) of study participants with diabetes who were taking antihypertensive therapy were obese (body mass index ≥ 30 kg / m2 ), whereas for those participants without these comorbidities, 56% were obese. The percentage of study participants achieving normal testosterone (plasma collected in NaF / EDTA tubes) after 90 days of treatment was 96.1% (plasma C avg0-24 = 393.5 ng / dL; quantification was by liquid chromatography-mass spectrometry (3,4). A study in 105 healthy eugonadal subjects found that the normal range for total testosterone was 222 to 800 ng / dL when using NaF / EDTA plasma sample collection tubes.

[0181] [Table 8]

[0182] Blood pressure and heart rate The change from baseline in 24-hour ambulatory systolic BP for oral testosterone undecanoate after 120 days of treatment was 1.7 mmHg, p=0.018 (Table 9). A smaller effect was seen for ambulatory diastolic BP, which was not statistically significant (Table 9). Results after 180 days of oral testosterone undecanoate therapy were comparable to those after 120 days (Table 9). The nighttime decrease in diastolic BP (daytime-nighttime / daytime BP x 100 (%)) was not altered by oral testosterone undecanoate therapy on the 120th day of the study (8.9% vs. 8.8% at baseline). A slight increase in 24-hour ambulatory heart rate was observed after 120 and 180 days of therapy (0.7 and 1.9 beats / min, respectively) (Table 9).

[0183] [Table 9]

[0184] [Table 10]

[0185] Ambulatory systolic and diastolic BP over 24 hours at baseline and at the end of the 120-day and 180-day treatment periods are shown in Figures 9A and 9B. 24-hour BP after 120 and 180 days of treatment with oral testosterone undecanoate was higher, mainly 13-16 hours after the start of ambulatory BP monitoring. The effect on 24-hour diastolic BP was lower than that for systolic BP, especially toward the end of the treatment period. Cumulative distribution function (CDF) curves for 24-hour ambulatory systolic and diastolic BP are shown in Figures 10A and 10B. For systolic BP, separation of the CDF curves for 120 and 180 days versus the baseline period was observed, mainly when the 24-hour systolic BP values ​​were <125 mmHg. Changes in 24-hour diastolic BP were negligible (Figures 10A and 10B).

[0186] Clinic blood pressure increased by 2.7 / 1.5 mmHg after 120 days of treatment with oral testosterone undecanoate and by 1.7 / 1.7 mmHg after 180 days of treatment with oral testosterone undecanoate (Table 9). Clinic pulse rate increased by 1.1 and 2.6 beats / min on days 120 and 180, respectively (Table 9).

[0187] Blood pressure changes in subgroups on antihypertensive therapy or with type 2 diabetes The changes from baseline in 24-hour blood pressure and heart rate at day 120 in study participants both with and without antihypertensive therapy and with and without type 2 diabetes are shown in Table 10. The changes from baseline in 24-hour systolic and diastolic BP and heart rate were greater in patients taking antihypertensive medications versus those without antihypertensive therapy.

[0188] [Table 11]

[0189] There were 33 study participants with diabetes mellitus and 120 without diabetes mellitus at baseline who had evaluable ambulatory BP data. Changes from baseline in 24-hour systolic and diastolic BP at day 120 were numerically greater, but not significant, in patients with type 2 diabetes versus those without type 2 diabetes. Similarly, changes in ambulatory heart rate were numerically greater in patients with diabetes versus those without diabetes.

[0190] Of note, for study participants with type 2 diabetes, 25 (74%) were on antihypertensive therapy, and therefore there is a substantial overlap between participants with diabetes and those on antihypertensive therapy. There were 89 subjects in the study who did not have antihypertensive medication at baseline, of which only 9 had diabetes mellitus. For these 89 subjects, the 95% confidence interval for the change from baseline in 24-hour systolic and diastolic BP at day 120 was 0.8 mmHg, which was not statistically significant (data not shown).

[0191] Blood pressure findings according to clinical features Changes in the primary endpoint according to baseline ambulatory systolic BP, age, dose of oral testosterone undecanoate, weight, and antihypertensive treatment status are shown in Table 11. Baseline blood pressure and hypertension treatment status were significantly associated with changes in 24-hour systolic BP at both days 120 and 180. No other clinical characteristics had a significant association with the primary endpoint at either days 120 or 180.

[0192] [Table 12]

[0193] Serum hemoglobin was 14.7 ± 1.1 g / dL at baseline, 15.1 ± 1.5 g / dL at day 90, and 15.2 ± 1.5 g / dL at day 180 (hemoglobin values ​​were not available at day 120). Hemoglobin levels at day 90 of the study were weakly but significantly associated with 24-h ambulatory systolic BP at days 120 and 180 (R 2 = 0.052, p = 0.0002 and R for day 180 2 = 0.049, p = 0.0005) (Figure 11). However, change from baseline in serum hemoglobin was not a predictor of change in 24-h ambulatory systolic BP in the study. Regression analysis of change from baseline in 24-h systolic BP after 120 days against 24-h testosterone mean concentrations (after 90 days) showed no association (R 2 = 0.009, p = 0.3109) (Figure 12). Testosterone undecanoate dose remained constant in this study from day 56 until the end of treatment (nominal 180 days).

[0194] Consideration Results of our blood pressure safety study demonstrated that the oral testosterone undecanoate formulation SOV2012-F1 was associated with a small increase in clinic and ambulatory systolic BP approximately 120 and 180 days after replacement therapy in hypogonadal men. No differences were observed between the 120-day and 180-day visits, suggesting that the drug's effect on BP reached a plateau by 120 days. The increase in systolic BP was greater than the increase in diastolic BP, both when measured at the clinical site and by 24-hour ambulatory BP monitoring. Small increases in clinic and ambulatory heart rate were also observed for this oral testosterone undecanoate. The increase in ambulatory systolic BP was inversely correlated with baseline levels of ambulatory BP (which may be partially related to regression to the mean) and antihypertensive treatment status, but did not correlate with changes in ambulatory heart rate, weight, diabetes mellitus, or hemoglobin or testosterone levels. These findings are significant because the correlation to heart rate may have suggested increased sympathetic nervous system activity, and the correlation with changes in weight or hemoglobin in men treated with oral testosterone undecanoate may have supported an increase in plasma volume as one possible mechanism for the small elevation in BP.

[0195] This study was designed to evaluate the change in 24-hour ambulatory BP as the primary endpoint in this study instead of the change in clinic BP. Of note, the US Food and Drug Administration advocates the use of ambulatory BP measurements in drug safety investigations because these devices have the potential to detect smaller BP changes with improved reproducibility compared to clinical BP measurements and are virtually free of placebo effects. As a result of the objectivity of ambulatory BP measurements, a placebo treatment arm for studies such as ours is not a requirement to provide evidence for modest to moderate BP effects. High frequency readings obtained over a 24-hour period improves the precision of BP safety studies and has the power to exclude BP changes of 3-4 mmHg. It is also noteworthy that the change in clinical BP was slightly greater than the change in 24-hour ambulatory BP in this study. This phenomenon is not uncommon and may be related to the "white coat" effect seen with clinical readings, but with ambulatory BP measurements, this effect disappears.

[0196] We observed a larger change from baseline in ambulatory BP in men taking antihypertensive medication and in men with type 2 diabetes. The mean change in ambulatory BP in those men on antihypertensive therapy was approximately 3.4 / 1.8 mmHg, while men not taking antihypertensive therapy had a substantially smaller, slight change of 0.7 / 0.0 mmHg. Similar findings were observed for patients both with and without diabetes, although a high proportion of study participants with diabetes were also taking antihypertensive therapy and are not truly separate subpopulations.

[0197] The 24-hour ambulatory BP increase in response to treatment in our study was modest (SBP 1.7 mmHg, 95% CI 0.3, 3.1) and lower than that from previous testosterone studies utilizing both clinic and ambulatory BP measurements. These previous studies used testosterone undecanoate (oral) and testosterone enanthate (subcutaneous) routes of administration and reported an ambulatory SBP increase of 4.9 and 3.7 mmHg, respectively. For the previously reported study of oral TU, the increase in ambulatory systolic BP for subjects receiving antihypertensive medication was 5.5 mmHg. The mechanism for the smaller increase in BP observed with SOV2012-F1 is not fully known and may be due in part to the presence of phytosterol esters in the formulation, which have been associated with lower BP.

[0198] It has been shown that a 3-5 mmHg increase in clinic systolic BP in large population prospective studies has a strong association with adverse cardiovascular events, especially heart failure and stroke. However, the clinical significance of the small increase in BP observed in hypogonadal men in our study is unclear, as there are data suggesting that men with testosterone deficiency have an elevated cardiovascular risk and that normalization of testosterone levels in hypogonadal men may be associated with reduced cardiovascular morbidity than men who remain at low testosterone levels. Nevertheless, careful clinical evaluation of possible increases in BP in hypogonadal men who require testosterone replacement, especially those with a history of hypertension, remains important in clinical practice.

[0199] conclusion In conclusion, this novel oral formulation of testosterone undecanoate administered at 100 mg once daily to 400 mg twice daily induced small increases in clinic and ambulatory BP. There was a minimal increase in ambulatory heart rate that was not associated with changes in ambulatory BP. Study participants with a history of hypertension taking antihypertensive therapy and study participants with type 2 diabetes had greater increases in both ambulatory BP and heart rate after long-term oral testosterone undecanoate therapy than study participants without these two comorbidities. Hypogonadal men who were not receiving antihypertensive medication had negligible changes in ambulatory BP and heart rate.

[0200] Example 5. Cmax and Cavg Measurement An oral TU formulation formulated as SOV-2012-F1 was administered to male subjects requiring testosterone replacement therapy. 1. The mean of the resulting population has a 0-24 hour Cmax / Cavg ratio of less than 2.5; 2. The mean of the resulting population has a 0-12 hour Cmax / Cavg ratio of less than 2.2; 3. The resulting population mean has a 12-24 hour Cmax / Cavg ratio of less than 2.2 when BID dosing is used; 4. The dose-adjusted dose is approximately 0.7 x 10^-6 / dL (393.3ng / dL / 571mg average dose). 5. The daily dose range is 100 mg to 800 mg TU / day; daily doses of 200 mg or more can be administered as a single dose or as a 50:50 split administered twice per day. Systolic blood pressure as assessed by ambulatory blood pressure monitoring (ABPM) after 6.4 months shows a mean increase of 1.7 mmHg and after 6 months a mean increase of 1.8 mmHg.

[0201] The advantages of a lower ratio A lower ratio has several advantages relative to QDs or BIDs, including the following:

[0202] More reliable dose setting: Given the shape of the adsorption and elimination portions of the pharmacokinetic curve, it is desirable to select a time or range of times for sampling testosterone concentrations that is convenient for the individual and the healthcare provider and has a low degree of variability. For example, if the Cmax / Cavg ratio is high, meaning a steep elimination portion of the PK curve, there will be variability in the T concentrations of samples taken for dose setting or periodic evaluation purposes due to factors such as the fat content of the meal, which affects the time of maximum concentration, variability in the exact sampling time, and individual differences in elimination rates. A lower Cmax / Cavg ratio mitigates each of these factors.

[0203] Broader time window for dose titration or periodic assessment sampling: The lower the Cmax / Cavg ratio, the slower the instantaneous T concentration changes and therefore the slower the elimination curve, allowing a wider window of time for sample collection; dose titration can be based on samples taken over a range of times, e.g., 3-5 hours or 3-6 hours, as demonstrated by follow-up studies.

[0204] More efficient conversion of prodrug dose to systemic T: A lower Cmax / Cavg ratio may be characteristic of more efficient use of the administered dose. However, other factors come into play, for example, a poorly absorbed dose will have a minimal increase over endogenous T levels and therefore exhibit a low Cmax / Cavg ratio. Apart from a given absorbed (relative to administered) dose, a lower Cmax ratio indicates a prolonged effect and is desirable. A lower Cmax / Cavg ratio indicates a higher percentage of time serum testosterone is within the normal range.

[0205] Advantages of a wider dose range The development of a formulation of TU with a broad range of effective doses provides advantages including:

[0206] A wider patient population can be treated: it is well known that individuals absorb TU and convert TU to T to different degrees, with some individuals needing much lower doses than others, while others need higher doses. For example, in the 2019 EXT study, among 130 subjects at day 90, 3 were at a dose level of 100 mg once daily (25% of the starting dose of 400 mg daily), and another 8 were at a daily dose of 200 mg (as 100 mg BID with meals). Thus, a dose that was 50% or less of the starting dose allowed treatment of 8+3=11;100%*11 / 130=8.5% of subjects titrated. Without a wide dose range, these subjects may have had T levels that were too high for the SOV2012-F1 formulation. In addition, 33 (25%) of the 130 subjects at day 90 were titrated to a total daily dose of 800 mg, double the starting daily dose of 400 mg. Thus, the broad dose ranges extending to 25% of the starting dose and 200% of the starting dose allowed more than 30% of subjects to receive an adequate dose. Without these broad dose ranges, some subjects would be at risk for higher than physiological levels of T Cavg, subnormal T Cavg levels, or Cmax levels above FDA-specified parameters.

[0207] Tolerance of extrinsic factors: Because TU absorption can also be affected by extrinsic factors such as diet and compliance, a wide dose range allows individuals who may have a suboptimal diet for TU absorption to be further titrated into the eugonadal range by reaching a wide dose range.

[0208] Dose correction Cavg The dose-corrected dose may be calculated as the average dose divided by the average T Cavg. This attribute attempts to characterize the efficiency of the formulation in delivering the active substance. However, the clinical trial design also influences the performance of the dose-corrected dose in that for formulations with a wide dose range, the dose-corrected dose varies widely across doses. The average dose-corrected Cavg for T plasma was 0.69 and for serum was 0.79. This difference reflects the known effect of measuring T in the presence of TU in the sample (LaChance).

[0209] These data are summarized in Tables 12-14 and Figures 13-17.

[0210] [Table 13]

[0211] [Table 14]

[0212] [Table 15]

[0213] Other embodiments While the invention has been described in relation to specific embodiments thereof, it will be understood that further modifications are possible, and this application is intended to cover any variations, uses, or adaptations of the invention in accordance with the principles of the invention, within known or customary practice in the art to which the invention pertains, including departures therefrom that may be applicable to the essential features hereinbefore described, and in accordance with the scope of the appended claims.

[0214] Other embodiments are within the scope of the claims.

Claims

A composition comprising testosterone undecanoate (TU) for use in the treatment of testosterone deficiency in a subject in need thereof, wherein: said use comprises: a) implementing a treatment regimen comprising orally administering 400 mg of testosterone undecanoate (TU) to said subject daily with a meal, wherein said TU is administered in said pharmaceutical composition comprising TU, a non-steroidal solubilizing agent effective for solubilizing said TU, and phytosterol or phytosterol ester; b) establishing a first steady-state serum concentration of testosterone; c) providing a first steady-state serum value of testosterone in said subject, measured about 3 to about 6 hours after administration of said pharmaceutical composition, after step (b); and d) implementing a first dose setting of said testosterone undecanoate including: i) if said first serum value of testosterone is less than about 400 / F + b ng / dL, orally administering about 600 mg of TU to said subject daily to establish a second steady-state serum value of testosterone higher than said first steady-state serum value of testosterone; ii) if said first serum value of testosterone is from about 400 / F + b ng / dL to about 900 / F + b ng / dL, continuing to orally administer about 400 mg of TU to said subject to maintain said first steady-state serum value of testosterone; or iii) if said first serum value of testosterone exceeds about 900 / F + b ng / dL, orally administering about 200 mg of TU to said subject to establish a second steady-state serum value of testosterone lower than said first steady-state serum value of testosterone. Claim 2 The composition for use according to claim 1, wherein step (a) comprises administering said pharmaceutical composition twice a day. Claim 3 a) The first dose is administered in the morning and the second dose is administered in the evening; and / or b) The composition for use according to claim 2, wherein said first dose comprises about 200 mg of TU and said second dose comprises about 200 mg of TU. Claim 4 After said first dose setting, i) is about 600 mg of TU administered daily to said subject, said first dose comprising about 300 mg of TU and said second dose comprising about 300 mg of TU? ii) about 400 mg of TU is administered daily to the subject, the first dose comprises about 200 mg of TU, and the second dose comprises about 200 mg of TU; or iii) about 200 mg of TU is administered daily to the subject, the first dose comprises about 100 mg of TU, and the second dose comprises about 100 mg of TU, a composition for use according to claim 3.

5. e) establishing a second steady-state serum concentration of testosterone; f) after step (e), providing a second steady-state serum value of testosterone in the subject; and g) implementing a second dose setting of the TU A composition for use according to any one of claims 1 to 4, further comprising.

6. After the first dose setting, about 600 mg of TU is administered daily to the subject, and a) if the second serum value of testosterone is less than about 400 / F + b ng / dL, orally administering about 800 mg of TU daily to the subject to establish a third steady-state serum value of testosterone higher than the second steady-state serum value of testosterone; b) if the second serum value of testosterone is between about 400 / F + b ng / dL and about 900 / F + b ng / dL, continuing to orally administer about 600 mg of TU daily to the subject to maintain the second steady-state serum value of testosterone; or c) if the second serum value of testosterone exceeds about 900 / F + b ng / dL, orally administering about 400 mg of TU daily to the subject to establish a third steady-state serum value of testosterone lower than the second steady-state serum value of testosterone, a composition for use according to claim 5.

7. After the first dose setting, about 400 mg of TU is administered daily to the subject, and a) if the second serum value of testosterone is less than about 400 / F + b ng / dL, orally administering about 600 mg of TU daily to the subject to establish a third steady-state serum value of testosterone higher than the second steady-state serum value of testosterone; b) if the second serum value of testosterone is between about 400 / F + b ng / dL and about 900 / F + b ng / dL, continuing to orally administer about 400 mg of TU daily to the subject to maintain the second steady-state serum value of testosterone; or c) If the second serum value of testosterone exceeds about 900 / F + b ng / dL, orally administer about 200 mg of TU to the subject daily to establish a third steady-state serum value of testosterone lower than the second steady-state serum value of testosterone, the composition for use according to claim 5.

8. After the first dose setting, about 200 mg of TU is administered to the subject daily, and a) If the second serum value of testosterone is less than about 400 / F + b ng / dL, orally administer about 400 mg of TU to the subject daily to establish a third steady-state serum value of testosterone higher than the second steady-state serum value of testosterone; b) If the second serum value of testosterone is between about 400 / F + b ng / dL and about 900 / F + b ng / dL, continue to orally administer about 200 mg of TU to the subject daily to maintain the second steady-state serum value of testosterone; or c) If the second serum value of testosterone exceeds about 900 / F + b ng / dL, orally administer about 100 mg of TU to the subject daily to establish a third steady-state serum value of testosterone lower than the second steady-state serum value of testosterone, the composition for use according to claim 5.

9. After the second dose setting, about 800 mg of TU is administered to the subject daily, the first dose includes about 400 mg of TU, and the second dose includes about 400 mg of TU, the composition for use according to claim 6.

10. After the second dose setting, about 100 mg of TU is administered to the subject daily, and the subject receives a single dose of about 100 mg of TU, the composition for use according to claim 8.

11. The pharmaceutical composition a) about 10% to about 25% by weight of solubilized testosterone undecanoate; b) about 5% to about 40% by weight of a hydrophilic surfactant; c) about 15% to about 65% by weight of a hydrophobic surfactant; d) about 2% to about 45% by weight of phytosterol ester; and e) about 0% to about 15% by weight of a solubilizer comprising, the composition for use according to any one of claims 1 to 10.

12. The pharmaceutical composition a) about 18.2% by weight of solubilized testosterone undecanoate; b) about 15.0% by weight of polyoxyl 40 hydrogenated castor oil; c) about 39.9% by weight of propylene glycol monolaurate; d) about 25.0% by weight of one or more phytosterol esters; and e) about 2.0% by weight of dl-alpha-tocopherol and / or its esters or acetates A composition for use according to claim 11, comprising.

13. a) The subject is a hypogonadal male; b) The subject has not been previously administered TU or other testosterone replacement therapy for a period of at least 7 days or for a period sufficient to completely wash out exogenous testosterone from the subject; and / or c) A composition for use according to any one of claims 1 to 12, which is administered to a population of human subjects.

14. a) The population includes at least 10 subjects, at least 50 subjects, at least 100 subjects, at least 200 subjects, at least 500 subjects or more than that; b) The use achieves an average Cavg in the serum normal range of about 300 ng / dL to about 1000 ng / dL in at least 75% of the population; c) The use achieves a Cmax of less than about 1500 ng / dL in at least 85% of the population; d) The use achieves a Cmax of about 1800 ng / dL to about 2500 ng / dL in 5% or less of the population; e) The use achieves a Cmax of more than about 2500 ng / dL in 0% or less of the population; f) The use reduces the average number of incorrect dose settings or the risk of incorrect dose settings per subject in the population to achieve said serum values of about 300 ng / dL to about 1000 ng / dL for a population that has not received a treatment regimen where the initial dose is not about 400 mg of TU and / or the steady-state testosterone serum value is not measured about 3 to about 6 hours after dosing; g) The use achieves an average Cavg in the serum normal range of about 300 ng / dL to about 1000 ng / dL in a greater number of subjects in the population compared to a treatment regimen where the initial dose is not about 400 mg of TU and / or the serum value is not measured about 3 to about 6 hours after dosing; h) The use achieves a Cmax of less than about 1500 ng / dL in a greater number of subjects in the population compared to the treatment regimen where the initial dose is not about 400 mg of TU and / or the serum value is not measured about 3 to about 6 hours after dosing; i) The use results in a Cmax of about 1800 ng / dL to about 2500 ng / dL in a smaller number of subjects in the population as compared to the treatment regimen where the initial dose is not about 400 mg of TU and / or the serum value is not measured about 3 to about 6 hours after administration; j) The use results in a Cmax of greater than about 2500 ng / dL in a smaller number of subjects in the population as compared to the treatment regimen where the initial dose is not about 400 mg of TU and / or the serum value is not measured about 3 to about 6 hours after administration; and / or k) The use reduces the risk of blood pressure increase in the population of human subjects, a composition for the use according to claim 13.

15. a) The systolic blood pressure during the day, the systolic blood pressure at night and / or the 24-hour average systolic blood pressure does not increase by more than 3 mmHg as compared to the blood pressure before the start of treatment in the population of human subjects; and / or b) The subject has diabetes or hypertension, and the systolic blood pressure during the day, the systolic blood pressure at night and / or the 24-hour average systolic blood pressure does not increase by more than 4 mmHg as compared to the blood pressure before the start of treatment in the population of human subjects, a composition for the use according to claim 14.

16. The average of the population is a) a 0 to 24-hour Cmax / Cavg ratio of less than 2.5; b) a 0 to 12-hour Cmax / Cavg ratio of less than 2.2; and / or c) a 12 to 24-hour Cmax / Cavg ratio of less than 2.2 for a composition for the use according to any one of claims 13 to 15.

17. The first serum value is a) measuring the testosterone concentration of serum coagulated at room temperature for about 30 minutes before centrifugation in a tube; b) measuring the testosterone concentration of plasma in a tube supplemented with EDTA and NaF and multiplying the testosterone concentration by the reciprocal (1 / F) of a predetermined coefficient F; or c) an equivalent method by which it is measured, a composition for the use according to any one of claims 1 to 16.

18. a) The subject is at risk of hypertension, heart attack or stroke; b) The subject suffers from low testosterone levels due to aging; c) The subject suffers from low testosterone levels due to a disease that reduces testosterone production; d) the subject has diabetes, hypertension, a metabolic disorder or is obese; e) the subject has been previously treated with antihypertensive drug therapy; f) the subject has osteoporosis, sexual function or libido, decreased muscle strength or muscle endurance, aplastic anemia, AIDS wasting syndrome, obstructive sleep apnea, a metabolic disorder, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH); and / or g) the subject is at risk of adverse events associated with testosterone, a composition for use according to any one of claims 1 to 17.

19. The method according to claim 18, wherein the diabetes is type 1 diabetes.

20. A composition comprising testosterone undecanoate (TU) for use in the treatment of testosterone deficiency in a subject in need thereof, wherein the use comprises a) implementing a treatment regimen comprising orally administering 400 mg of testosterone undecanoate (TU) daily to the subject with a meal, wherein the TU is administered in the pharmaceutical composition comprising TU, a non-steroidal solubilizing agent effective for solubilizing the TU and phytosterol or phytosterol ester; b) establishing a first steady-state serum concentration of testosterone; c) providing a first steady-state serum value of testosterone in the subject, measured about 3 to about 6 hours after administration of the pharmaceutical composition, after step (b); and d) implementing a first dose setting of the testosterone undecanoate including i) if the first serum value of testosterone is less than about 460 ng / dL, orally administering about 600 mg of TU daily to the subject to establish a second steady-state serum value of testosterone higher than the first steady-state serum value of testosterone; ii) if the first serum value of testosterone is between about 460 ng / dL and about 971 ng / dL, continuing to orally administer about 400 mg of TU daily to the subject to maintain the first steady-state serum value of testosterone; or iii) if the first serum value of testosterone exceeds about 971 ng / dL, orally administering about 200 mg of TU daily to the subject to establish a second steady-state serum value of testosterone lower than the first steady-state serum value of testosterone; the subject is During antihypertensive therapy and showing an average change of 3.4 mmHg or less in systolic blood pressure, an average change of 1.8 mmHg or less in diastolic blood pressure, and / or an average change of 1.3 beats per minute or less in heart rate; and / or A composition having true diabetes and showing an average change of 3.0 mmHg or less in systolic blood pressure, an average change of 1.7 mmHg or less in diastolic blood pressure, and / or an average change of 1.9 beats per minute or less in heart rate.

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