Treatment of prostate cancer
Methods for treating prostate cancer, including advanced prostate cancer, in a subject in need thereof, include administering once-daily to the subject, at least 80 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof. Another method includes: administering once-daily to the subject in need thereof, an oral load dose formulation having from 240 mg to 480 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and thereafter administering once-daily to the subject, an oral maintenance dose formulation having 80 mg to 160 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof.
1. A method for treating advanced prostate cancer in a subject in need thereof, the method comprising:
orally administering once daily to the subject N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof;
wherein on a first treatment day the subject is administered an oral loading dose of 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, and
wherein on all subsequent treatment days the subject is administered an oral maintenance dose of 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof;
wherein the oral loading dose provides a PK profile in which the subject's plasma AUC(0-24) of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea is greater than or equal to the subject's steady state AUC 24 reached after administration of the oral maintenance doses.
2. The method according to claim 1 , wherein steady state is reached within 10 days after the first treatment day.
3. A method of treating hormone dependent prostate cancer in a subject in need thereof, the method comprising:
orally administering once-daily to the subject N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof;
wherein on a first treatment day the subject is administered an oral loading dose of 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, and
wherein on all subsequent treatment days the subject is administered an oral maintenance dose of 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof;
wherein the oral load dose provides a PK profile in which the subject's plasma AUC(0-24) of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea is greater than or equal to the subject's steady state AUC 24 reached after administration of the oral maintenance doses.
4. The method according to claim 3 , wherein steady state is reached by the tenth treatment day.
5. The method of claim 1 , wherein the subject's serum testosterone concentration is below 50 ng/dL by the eighth treatment day.
6. The method of claim 5 , wherein the subject's serum testosterone concentration is below 50 ng/dL by the fourth treatment day.
7. The method of claim 6 , wherein the subject's serum testosterone concentration is below 50 ng/dL within 24 to 48 hours after the first treatment day.
8. The method of claim 5 , wherein the subject's serum testosterone concentration is below 20 ng/dL within five weeks after the first treatment day.
9. The method of claim 5 , wherein the subject's serum testosterone concentration is below 20 ng/dL within three weeks after the first treatment day.
10. The method of claim 5 , wherein the subject's serum testosterone concentration is below 20 ng/dL within two weeks after the first treatment day.
11. The method of claim 5 , wherein the subject's serum testosterone concentration is below 20 ng/dL within one week after the first treatment day.
12. The method of claim 5 , wherein the subject's serum testosterone concentration is below 20 ng/dL within 4 days after the first treatment day.
13. The method of claim 6 , wherein the subject's serum testosterone concentration is below 20 ng/dL within five weeks after the first treatment day.
14. The method of claim 6 , wherein the subject's serum testosterone concentration is below 20 ng/dL within three weeks after the first treatment day.
15. The method of claim 6 , wherein the subject's serum testosterone concentration is below 20 ng/dL within two weeks after the first treatment day.
16. The method of claim 6 , wherein the subject's serum testosterone concentration is below 20 ng/dL within one week after the first treatment day.
17. The method of claim 1 , wherein the oral loading dose is administered as three, 120 mg doses of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof.
18. The method of claim 3 , wherein the oral loading dose is administered as three, 120 mg doses of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof.