Compositions and methods for treating centrally mediated nausea and vomiting

1. A method of treating nausea and vomiting from an emesis-inducing event for a period of five consecutive days in a patient in need thereof, comprising administering to said patient netupitant or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount which is effective to treat nausea and vomiting during the acute and delayed phases of emesis, and which enters the systemic circulation, crosses the blood brain barrier and occupies 70% or more of NK 1 receptors in the striatum seventy-two hours after said administration, wherein a single dose of netupitant or pharmaceutically acceptable salt thereof is administered on day one of said five consecutive days, no further netupitant or pharmaceutically acceptable salt thereof is administered during said five consecutive days, and said single dose of netupitant or pharmaceutically acceptable salt thereof if effective to treat said nausea and vomiting for said five consecutive days.

2. The method of claim 1 , wherein said netupitant occupies 80% or more of NK 1 receptors in the striatum seventy-two hours after said administration.

3. The method of claim 1 , further comprising: a) administering to said patient on day one a first dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant, wherein said first dose comprises from 50 to 70% of a minimum effective dose when administered alone; and b) if said patient is subject to highly emetogenic chemotherapy, administering to said patient, on days two, three and four, a second dose of dexamethasone which is ineffective against nausea and vomiting when administered alone, but effective against nausea and vomiting when administered in combination with said netupitant, wherein said second dose comprises from 40 to 60% of a minimum effective dose when administered alone.

4. The method of claim 1 wherein: a) only one dose of netupitant is administered during said five days on day one, comprising about 300 mg. of netupitant as the free base; and b) administering about 12 mg. of dexamethasone on day one; and c) if said patient is undergoing highly emetogenic chemotherapy, administering about 8 mg. of dexamethasone on days two, three and four.

5. The method of claim 1 wherein said nausea and vomiting is chemotherapy induced nausea and vomiting (“CINV”), radiation therapy induced nausea and vomiting (“RINV”), or post-operative nausea and vomiting (“PONV”).

6. The method of claim 1 wherein said nausea and vomiting is induced by moderately or highly emetogenic chemotherapy.

7. The method of claim 1 comprising administering moderately or highly emetogenic chemotherapy within from about one hour to about two hours of said administration of said netupitant or pharmaceutically acceptable salt thereof.

8. The method of claim 1 comprising treating nausea and vomiting in response to highly emetogenic chemotherapy during the acute phase, or in response to highly emetogenic chemotherapy during the delayed phase, or in response to moderately emetogenic chemotherapy during the acute phase, or in response to moderately emetogenic chemotherapy during the delayed phase.

9. The method of claim 1 , comprising administering from about 200 to about 400 mg of netupitant as the free base.

10. The method of claim 1 , comprising orally administering about 300 mg of netupitant as the free base.

11. A method of treating nausea and vomiting in response to an emesis-inducing event for a period of five consecutive days in a patient in need thereof, comprising administering to said patient netupitant or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount which is effective to treat nausea and vomiting during the acute and delayed phases of emesis, wherein said therapeutically effective amount of netupitant or pharmaceutically acceptable salt thereof is administered on day one of said five consecutive days, no further netupitant or pharmaceutically acceptable salt thereof is administered during said five consecutive days, and said single dose of netupitant or pharmaceutically acceptable salt thereof if effective to treat said nausea and vomiting for said five consecutive days.

12. The method of claim 11 , comprising orally administering from about 200 to about 400 mg of netupitant as the free base.

13. The method of claim 11 , comprising orally administering about 300 mg of netupitant as the free base.

14. The method of claim 11 , wherein when said emesis inducing event comprises highly emetic chemotherapy, and the chemotherapy is selected from the group consisting of carmustine, cisplatin, cyclophosphamide≥1500 mg/m 2 , dacarbazine, dactinomycin, mechlorethamine, streptozotocin and combinations thereof.

15. The method of claim 11 , wherein when said emesis inducing event comprises moderately emetic chemotherapy, and the chemotherapy is selected from the group consisting of carboplatin, cyclophosphamide<1500 mg/m 2 , cytarabine>1 mg/m 2 , daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin and combinations thereof.

16. The method of claim 11 , wherein said emesis inducing event comprises chemotherapy selected from the group consisting of carboplatin, cyclophosphamide, cytarabine>1 mg/m 2 , daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, carmustine, cisplatin, dacarbazine, dactinomycin, mechlorethamine, streptozotocin, oxaliplatin and combinations thereof.

17. The method of claim 11 , for the treatment of CINV defined as no emetic episodes and no use of rescue medication following chemotherapy.

18. The method of claim 17 , wherein said netupitant occupies at least 70% of said patient's striatum NK1 receptors ninety-six hours after said administration.

19. The method of claim 11 , wherein said emesis inducing event is highly emetogenic chemotherapy, and said regimen is effective to prevent or reduce the severity of nausea during the acute and delayed phases.

20. The method of claim 11 , wherein said emesis inducing event is moderately emetogenic chemotherapy, and said regimen is effective to prevent or reduce the severity of nausea during the acute and delayed phases.

21. The method of claim 11 , wherein said emesis inducing event comprises cisplatin.

22. The method of claim 11 , wherein said emesis inducing event comprises carboplatin, cisplatin, oxaliplatin, or doxorubicin.

23. The method of claim 11 , wherein said emesis inducing event comprises cyclophosphamide.