Claims for Patent: 11,110,081

Summary for Patent: 11,110,081

Title:	Tacrolimus for improved treatment of transplant patients
Abstract:	An extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for a once daily immunosuppressive treatment of a patient in need thereof, preferable a kidney or liver transplant patient. The dosage form releases the active substance over an extended period of time. It also provides improved pharmacokinetic parameters due to an extended and constant in vivo release including substantial decreased peak concentrations, despite increased bioavailability, substantial extended times for maximal concentration, and higher minimal concentrations when compared with conventional immediate release dosage forms and a recent modified release tacrolimus dosage form.
Inventor(s):	Gordon; Robert D. (Sandy Springs, GA), Holm; Per (Vanlose, DK), Lademann; Anne-Marie (Klampenborg, DK), Norling; Tomas (Lyngby, DK)
Assignee:	VELOXIS PHARMACEUTICALS, INC. (Cary, NC)
Application Number:	17/085,291
Patent Claims:	1. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, and (ii) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours. 2. The method of claim 1, wherein T.sub.max is 8.55.+-.2.72 hours. 3. The method of claim 1, wherein T.sub.max is 6.00 to 10.02 hours. 4. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, and (iii) the patient is concomitantly treated with mycophenolate mofetil. 5. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, and (iii) the patient is concomitantly treated with a corticosteroid. 6. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, and (iii) the patient is African-American. 7. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, and (iii) the plasma concentration of tacrolimus in the patient is maintained at a therapeutically effective amount without inducing nephrotoxicity or neurotoxicity. 8. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, (iii) at least 8% of the tacrolimus in each extended release composition is released at the 4 hour time point, (iv) 40% of the tacrolimus is released within 10 to 14 hours, and the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 9. The method of claim 8, wherein T.sub.max is 6.00 to 10.02 hours. 10. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, (iii) at least 8% of the tacrolimus in each extended release composition is released at the 4 hour time point, (iv) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, and (v) the patient is concomitantly treated with mycophenolate mofetil. 11. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, (iii) at least 8% of the tacrolimus in each extended release composition is released at the 4 hour time point, (iv) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, and (v) the patient is concomitantly treated with a corticosteroid. 12. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, (iii) at least 8% of the tacrolimus in each extended release composition is released at the 4 hour time point, (iv) the T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours, and (v) the patient is African-American. 13. The method of claim 8, wherein the plasma concentration of tacrolimus in the patient is maintained at a therapeutically effective amount without inducing nephrotoxicity or neurotoxicity. 14. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein the initial dose of tacrolimus is 0.14 mg/kg/day, and the target trough concentration for the tacrolimus is 5-10 ng/mL. 15. The method of claim 14, wherein at least 8% of the tacrolimus in each extended release composition is released at the 4 hour time point. 16. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, and (iii) the in vivo release of each composition after oral administration takes place substantially in the colon. 17. The method of claim 14, wherein the in vivo release of each composition after oral administration takes place substantially in one or more of the colon ascendens, colon transversum and colon descendens. 18. The method of claim 14, wherein (a) at least 8% of the tacrolimus is released at the 4 hour time point after administration of each composition, (b) less than 25% of the tacrolimus is released at the 5 hour time point, (c) 40% of the tacrolimus is released within 10 to 14 hours, (d) 63.5% or less of the tacrolimus is released at the 12 hour time point, and (e) each composition releases the tacrolimus with a substantial zero order release profile over an extended period of time defined by the release from the 8 hours time point to the 15 hours time point, the substantial zero order release being defined as a linear release profile with a deviation of at the most .+-.15%, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 19. The method of claim 14, which when administered once daily in steady state to a healthy subject or a patient, the swing of the blood concentrations of tacrolimus measured as (C.sub.max-C.sub.min)/C.sub.min is less than the swing observed when administering either the tacrolimus dosage form approved by the European Agency for the Evaluation of Medicinal Products (EMEA) on Apr. 23, 2007 or tacrolimus dosage form approved under U.S. New Drug Application No. 050708 in a once daily regimen and being determined under similar conditions and administered in similar molecular daily dosages of the tacrolimus. 20. The method of claim 14, wherein T.sub.max on day 1, when administered under fasting conditions, is between 4 hours and 24 hours. 21. The method of claim 14, wherein 40% of the tacrolimus in each extended release composition is released within 11 to 13 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 22. The method of claim 14, wherein 50% of the tacrolimus in each extended release composition is released within 13 to 17 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 23. The method of claim 14, wherein (a) at least 8% of the tacrolimus is released at the 4 hour time point after administration of each composition, (b) less than 25% of the tacrolimus is released at the 5 hour time point, (c) 50% of the tacrolimus is released within 13 to 17 hours, (d) 63.5% or less of the tacrolimus is released at the 12 hour time point, and (e) each composition releases the tacrolimus with a substantial zero order release profile over an extended period of time defined by the release from the 8 hours time point to the 15 hours time point, the substantial zero order release being defined as a linear release profile with a deviation of at the most .+-.15%, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 24. The method of claim 23, wherein 50% of the tacrolimus in each extended release composition is released within 14 to 16 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 25. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, and (iii) the patient is concomitantly treated with mycophenolate mofetil. 26. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, and (iii) the patient is concomitantly treated with a corticosteroid. 27. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, and (iii) the patient is African-American. 28. A method of prophylaxis of organ rejection in a de novo kidney transplant patient comprising once daily orally administering to the patient an effective amount of tacrolimus in the form of one or more extended release compositions comprising tacrolimus, wherein (i) the initial dose of tacrolimus is 0.14 mg/kg/day, (ii) the target trough concentration for the tacrolimus is 5-10 ng/mL, and (iii) the plasma concentration of tacrolimus in the patient is maintained at a therapeutically effective amount without inducing nephrotoxicity or neurotoxicity.