Claims for Patent: 12,403,146

Summary for Patent: 12,403,146

Title:	Preferred oral testosterone undecanoate therapy to achieve testosterone replacement treatment
Abstract:	The present invention features new testosterone undecanoate (TU) dosing regimens, e.g., for testosterone replacement therapy. The TU may be formulated with phytosterols or phytosterol esters.
Inventor(s):	Om Dhingra, James S. Bernstein
Assignee:	Marius Pharmaceuticals LLC
Application Number:	US17/085,824
Patent Claims:	1. A method of treating testosterone deficiency in a subject in need thereof, the method comprising: a) performing a treatment regimen comprising orally administering to the subject 400 mg of testosterone undecanoate (TU) daily with a meal, wherein the TU is administered in a pharmaceutical composition comprising TU, a non-sterol solubilizing agent effective for solubilization of the TU, and a phytosterol or phytosterol ester; b) establishing a first steady state serum concentration of testosterone; c) following step (b), providing a first steady state Serum Value of testosterone in the subject that is measured from about 3 hours to about 6 hours after administration of the pharmaceutical composition; and d) performing a first titration of the testosterone undecanoate, wherein: i) if the first Serum Value of testosterone is less than about 460 ng/dl, then orally administering to the subject about 600 mg TU daily to establish a second steady state Serum Value of testosterone that is higher than the first steady state Serum Value of testosterone; ii) if the first Serum Value of testosterone is from about 460 ng/dl to about 971 ng/dl, then continuing to orally administer to the subject about 400 mg TU daily to maintain the first steady state Serum Value of testosterone; or iii) if the first Serum Value of testosterone is greater than about 971 ng/dl, then orally administering to the subject about 200 mg TU daily to establish a second steady state Serum Value of testosterone that is lower than the first steady state Serum Value of testosterone. 2. The method of claim 1, wherein step (a) comprises administering the pharmaceutical composition twice daily. 3. The method of claim 2, wherein: a) a first dose is administered in the morning and a second dose is administered in the evening; and/or b) the first dose comprises about 200 mg TU, and the second dose comprises about 200 mg TU. 4. The method of claim 3, wherein following the first titration, i) about 600 mg TU is administered daily to the subject, and the first dose comprises about 300 mg TU, and the second dose comprises about 300 mg TU; ii) about 400 mg TU is administered daily to the subject, and the first dose comprises about 200 mg TU, and the second dose comprises about 200 mg TU; or iii) about 200 mg TU is administered daily to the subject, and the first dose comprises about 100 mg TU, and the second dose comprises about 100 mg TU. 5. The method of claim 1, further comprising: e) establishing a second steady state serum concentration of testosterone; f) following step (e), providing a second steady state Serum Value of testosterone in the subject; and g) performing a second titration of the TU. 6. The method of claim 5, wherein following the first titration, about 600 mg TU is administered daily to the subject, and a) if the second Serum Value of testosterone is less than about 460 ng/dL, then orally administering about 800 mg TU daily to the subject to establish a third steady state Serum Value of testosterone that is higher than the second steady state Serum Value of testosterone; b) if the second Serum Value of testosterone is from about 460 ng/dL to about 971 ng/dL, then continuing to orally administer about 600 mg TU daily to the subject to maintain the second steady state Serum Value of testosterone; or c) if the second Serum Value of testosterone is greater than about 971 ng/dL, then orally administering about 400 mg TU daily to the subject to establish a third steady state Serum Value of testosterone that is lower than the second steady state Serum Value of testosterone. 7. The method of claim 5, wherein following the first titration, about 400 mg TU is administered daily to the subject, and a) if the second Serum Value of testosterone is less than about 460 ng/dL, then orally administering about 600 mg TU daily to the subject to establish a third steady state Serum Value of testosterone that is higher than the second steady state Serum Value of testosterone; b) if the second Serum Value of testosterone is from about 460 ng/dL to about 971 ng/dL, then continuing to orally administer about 400 mg TU daily to the subject to maintain the second steady state Serum Value of testosterone; or c) if the second Serum Value of testosterone is greater than about 971 ng/dL, orally administering about 200 mg TU daily to the subject to establish a third steady state Serum Value of testosterone that is lower than the second steady state Serum Value of testosterone. 8. The method of claim 7, wherein following the first titration, about 200 mg TU is administered daily to the subject, and a) if the second Serum Value of testosterone is less than about 460 ng/dL, orally administering about 400 mg TU daily to the subject to establish a third steady state Serum Value of testosterone that is higher than the second steady state Serum Value of testosterone; b) if the second Serum Value of testosterone is from about 460 ng/dL to about 971 ng/dL, then continuing to orally administer about 200 mg TU daily to the subject to maintain the second steady state Serum Value of testosterone; or c) if the second Serum Value of testosterone is greater than about 971 ng/dL, orally administering about 100 mg TU daily to the subject to establish a third steady state Serum Value of testosterone that is lower than the second steady state Serum Value of testosterone. 9. The method of claim 6, wherein following the second titration, about 800 mg TU is administered daily to the subject, and the first dose comprises about 400 mg TU, and the second dose comprises about 400 mg TU. 10. The method of claim 7, wherein following the second titration, about 100 mg TU is administered daily to the subject, and the subject receives a single dose of about 100 mg TU. 11. The method of claim 1, wherein: a) the first Serum Value of testosterone is measured prior to day 21 of the treatment regimen; and/or b) the first titration is performed on from about day 7 to about day 35 of the treatment regimen. 12. The method of claim 11, wherein: a) the first Serum Value of testosterone is measured on about day 7 of the treatment regimen; and/or b) the first titration is performed on about day 28 of the treatment regimen. 13. The method of claim 1, wherein the pharmaceutical composition comprises: a) from about 10% to about 25% by weight of solubilized testosterone undecanoate; b) from about 5% to about 40% by weight of a hydrophilic surfactant; c) from about 15% to about 65% by weight of a hydrophobic surfactant; d) from about 2% to about 45% by weight of phytosterol esters; and e) from about 0% to about 15% by weight of a solubilizer. 14. The method of claim 13, wherein the pharmaceutical composition comprises: 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 di-alpha-tocopherol and/or an ester or acetate thereof. 15. The method of claim 1, wherein: a) the subject is a hypogonadal male; b) the subject has not previously been administered TU or other testosterone replacement therapy for a period of at least seven days or a period of time sufficient to completely wash exogenous testosterone from the subject; and/or c) the method is performed on a population of human subjects. 16. The method of claim 15, wherein: a) the population comprises at least 10 subjects, at least 50 subjects, at least 100 subjects, at least 200 subjects, at least 500 subjects, or more; b) the method achieves a 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 method achieves a Cmax of less than about 1500 ng/dL in at least 85% of the population; d) the method achieves a Cmax of from about 1800 ng/dL to about 2500 ng/dL in no more than 5% of the population; e) the method achieves a Cmax of greater than about 2500 ng/dL in no more than 0% of the population; f) the method reduces an average number of incorrect titrations or the risk of incorrect titrations per subject in the population in order to achieve a steady state testosterone Serum Value of from about 300 ng/dL to about 1000 ng/dl relative to a population receiving a treatment regimen in which an initial dosage is not about 400 mg TU and/or the Serum Value is not measured from about 3 hours to about 6 hours after administration g) the method achieves a 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 as compared to a treatment regimen in which an initial dosage is not about 400 mg TU and/or the Serum Value is not measured from about 3 hours to about 6 hours after administration; h) the method achieves a Cmax of less than about 1500 ng/dL in a greater number of subjects in the population as compared to the treatment regimen in which the initial dosage is not about 400 mg TU and/or the Serum Value is not measured from about 3 hours to about 6 hours after administration; i) The method achieves a Cmax of from about 1800 ng/dL to about 2500 ng/dL in a fewer number of subjects in the population as compared to the treatment regimen in which the initial dosage is not about 400 mg TU and/or the Serum Value is not measured from about 3 hours to about 6 hours after administration; j) the method achieves a Cmax of greater than about 2500 ng/dL in a fewer number of subjects in the population as compared to the treatment regimen in which the initial dosage is not about 400 mg TU and/or the Serum Value is not measured from about 3 hours to about 6 hours after administration; and/or k) the method decreases the risk of elevated blood pressure of the population of human subjects. 17. The method of claim 16, wherein the daytime systolic blood pressure, night time systolic blood pressure, and/or 24-hour average systolic blood pressure does not increase by more than 3 mmHg as compared to the blood pressure before onset of treatment in the population of human subjects. 18. The method of claim 1, wherein the first Serum Value is measured by: measuring testosterone concentration of serum clotted at room temperature for about 30 minutes prior to centrifugation in a tube. 19. The method of claim 5, wherein the second Serum Value is measured by: measuring testosterone concentration of serum clotted at room temperature for about 30 minutes prior to centrifugation in a tube. 20. The method of claim 1, wherein the first steady state Serum Value of testosterone in the subject is measured from about 3 hours to about 5 hours after administration of the pharmaceutical composition. 21. The method of claim 1, wherein the second steady state Serum Value of testosterone in the subject is measured from about 3 hours to about 5 hours after administration of the pharmaceutical composition.