Claims for Patent: 9,186,357

Summary for Patent: 9,186,357

Title:	Compositions and methods for treating centrally mediated nausea and vomiting
Abstract:	Provided are compositions and methods for treating or preventing nausea and vomiting in patients undergoing chemotherapy, radiotherapy, or surgery.
Inventor(s):	Trento; Fabio (Como, IT), Cantoreggi; Sergio (Cagiallo, CH), Rossi; Giorgia (Como, IT), Cannella; Roberta (Varese, IT), Bonadeo; Daniele (Varese, IT)
Assignee:	HELSINN HEALTHCARE SA (Lugano/Pazzallo, CH)
Application Number:	14/069,927
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,186,357
Patent Claims:	1. A method of treating chemotherapy induced nausea and vomiting (CINV) comprising administering to a subject receiving chemotherapy a regimen of palonosetron, netupitant and dexamethasone. 2. A method of treating chemotherapy induced nausea and vomiting (CINV) in a subject receiving chemotherapy comprising administering to a subject receiving chemotherapy a regimen of netupitant and a sub-therapeutic dose of dexamethasone. 3. The method of claim 2, wherein the sub-therapeutic dose of dexamethasone comprises from about 50 to 70% of a minimum effective dose when administered alone against CINV. 4. A method of treating chemotherapy induced nausea and vomiting (CINV) comprising inducing in a subject receiving chemotherapy blood levels of palonosetron and netupitant effective to treat said CINV. 5. The method of claim 1, wherein the chemotherapy comprises moderately or highly emetogenic chemotherapy. 6. The method of claim 1, wherein said chemotherapy comprises carboplatin. 7. The method of claim 1, wherein the netupitant and palonosetron are administered no more than one hour prior to administration of the chemotherapy. 8. The method of claim 1, wherein when said chemotherapy is highly emetic chemotherapy, the chemotherapy is selected from the group consisting of carmustine, cisplatin, cyclophosphamide.gtoreq.1500 mg/m.sup.2, dacarbazine, dactinomycin, mechlorethamine, streptozotocin and combinations thereof. 9. The method of claim 1, wherein when said chemotherapy is moderately emetic chemotherapy, the chemotherapy is selected from the group consisting of carboplatin, cyclophosphamide<1500 mg/m.sup.2, cytarabine>1 mg/m.sup.2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin and combinations thereof. 10. The method of claim 1, wherein said chemotherapy is selected from the group consisting of carboplatin, cyclophosphamide, cytarabine>1 mg/m.sup.2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, carmustine, cisplatin, dacarbazine, dactinomycin, mechlorethamine, streptozotocin, oxaliplatin and combinations thereof. 11. The method of claim 2, wherein when said chemotherapy is highly emetic chemotherapy, the chemotherapy is selected from the group consisting of carmustine, cisplatin, cyclophosphamide.gtoreq.1500 mg/m.sup.2, dacarbazine, dactinomycin, mechlorethamine, streptozotocin and combinations thereof. 12. The method of claim 2, wherein when said chemotherapy is moderately emetic chemotherapy, the chemotherapy is selected from the group consisting of carboplatin, cyclophosphamide<1500 mg/m.sup.2, cytarabine>1 mg/m.sup.2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin and combinations thereof. 13. The method of claim 2, wherein said chemotherapy is selected from the group consisting of carboplatin, cyclophosphamide, cytarabine>1 mg/m.sup.2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, carmustine, cisplatin, dacarbazine, dactinomycin, mechlorethamine, streptozotocin, oxaliplatin and combinations thereof. 14. The method of claim 4, wherein when said chemotherapy is highly emetic chemotherapy, the chemotherapy is selected from the group consisting of carmustine, cisplatin, cyclophosphamide.gtoreq.1500 mg/m.sup.2, dacarbazine, dactinomycin, mechlorethamine, streptozotocin and combinations thereof. 15. The method of claim 4, wherein when said chemotherapy is moderately emetic chemotherapy, the chemotherapy is selected from the group consisting of carboplatin, cyclophosphamide<1500 mg/m.sup.2, cytarabine>1 mg/m.sup.2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin and combinations thereof. 16. The method of claim 4, wherein said chemotherapy is selected from the group consisting of carboplatin, cyclophosphamide, cytarabine>1 mg/m.sup.2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, carmustine, cisplatin, dacarbazine, dactinomycin, mechlorethamine, streptozotocin, oxaliplatin and combinations thereof. 17. The method of claim 1, wherein said treatment of CINV is defined as no emetic episodes and no use of rescue medication following said chemotherapy. 18. The method of claim 1, wherein: a) said regimen comprises a single administration of netupitant or pharmaceutically acceptable salt thereof and a single administration of palonosetron or pharmaceutically acceptable salt thereof; b) said netupitant or pharmaceutically acceptable salt thereof and said palonosetron or pharmaceutically acceptable salt thereof are administered concomitantly and prior to said chemotherapy, without administering a second dose of either for at least five days after said chemotherapy; and c) said regimen is effective to treat said CINV for a five day period after said chemotherapy. 19. The method of claim 1, wherein: a) said treatment of CINV is defined as no emetic episodes and no use of rescue medication following said chemotherapy; b) said regimen comprises a single administration of netupitant or pharmaceutically acceptable salt thereof and a single administration of palonosetron or pharmaceutically acceptable salt thereof; c) said netupitant or pharmaceutically acceptable salt thereof and said palonosetron or pharmaceutically acceptable salt thereof are administered concomitantly and prior to said chemotherapy, without administering a second dose of either for at least five days after said chemotherapy; and d) said regimen is effective to treat said CINV for a five day period after said chemotherapy. 20. The method of claim 19, wherein: a) said netupitant is administered orally as the free base in a dose of from about 200 mg to about 400 mg; and b) said palonosetron is administered orally as palonosetron hydrochloride in a dose of from about 0.25 mg to about 0.75 mg based on the weight of the free base. 21. The method of claim 19, wherein: a) said netupitant is administered orally as the free base in a dose of about 300 mg; b) said palonosetron is administered orally as palonosetron hydrochloride in a dose of about 0.50 mg based on the weight of the free base; and c) said netupitant and palonosetron are administered as a single unit dosage form less than 2 hours prior to said chemotherapy. 22. The method of claim 19, wherein: a) said chemotherapy comprises moderately emetogenic chemotherapy; b) said netupitant is administered orally as the free base in a dose of about 300 mg; c) said palonosetron is administered orally as palonosetron hydrochloride in a dose of about 0.50 mg based on the weight of the free base; d) said netupitant and palonosetron are administered as a combination unit dosage form less than 2 hours prior to said chemotherapy; and e) said dexamethasone is administered in a dose of about 12 mg, in a dosage form independent of said combination unit dosage form, less than 2 hours prior to said chemotherapy. 23. The method of claim 19, wherein: a) said chemotherapy comprises highly emetogenic chemotherapy; b) said netupitant is administered orally as the free base in a dose of about 300 mg; c) said palonosetron is administered orally as palonosetron hydrochloride in a dose of about 0.50 mg based on the weight of the free base; d) said netupitant and palonosetron are administered as a combination unit dosage form less than 2 hours prior to said chemotherapy; e) said dexamethasone is administered in a dose of about 12 mg, in a dosage form independent of said combination unit dosage form, less than 2 hours prior to said chemotherapy; and f) said dexamethasone is further administered in a dose of about 8 mg on days 2, 3 and 4 following said chemotherapy. 24. The method of claim 19, wherein said netupitant occupies at least 70% of said patient's striatum NK1 receptors ninety-six hours after said administration. 25. The method of claim 19, wherein: a) said chemotherapy is highly emetogenic chemotherapy; and b) said netupitant is effective to treat said CINV during the acute and delayed phases of said CINV. 26. The method of claim 19, wherein: a) said chemotherapy is highly emetogenic chemotherapy; and b) said regimen is effective to prevent nausea or reduce the severity of nausea in said patient during the acute and delayed phases of said CINV. 27. The method of claim 19, wherein: a) said chemotherapy is moderately emetogenic chemotherapy; and b) said regimen is effective to prevent nausea or reduce the severity of nausea in said patient during the acute and delayed phases of said CINV. 28. The method of claim 19, wherein (3S)-3-[(3aS)-1-oxo-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinoline-2-yl]- -1-azoniabicyclo[2.2.2]octan-1-olate is substantially absent from said palonosetron. 29. The method of claim 19, wherein said netupitant occupies at least 70% of said patient's striatum NK1 receptors ninety-six hours after said administration. 30. The method of claim 19, wherein said chemotherapy comprises cisplatin. 31. The method of claim 19, wherein said chemotherapy comprises carboplatin, cisplatin, oxaliplatin, or doxorubicin. 32. The method of claim 19, wherein said chemotherapy comprises cyclophosphamide. 33. The method of claim 21, wherein: a) said chemotherapy is highly emetogenic chemotherapy; and b) said netupitant is effective to treat said CINV during the acute and delayed phases of said CINV. 34. The method of claim 21, wherein: a) said chemotherapy is highly emetogenic chemotherapy; and b) said regimen is effective to prevent nausea or reduce the severity of nausea in said patient during the acute and delayed phases of said CINV. 35. The method of claim 21, wherein: a) said chemotherapy is moderately emetogenic chemotherapy; and b) said regimen is effective to prevent nausea or reduce the severity of nausea in said patient during the acute and delayed phases of said CINV. 36. The method of claim 21, wherein said netupitant occupies at least 70% of said patient's striatum NK1 receptors ninety-six hours after said administration. 37. The method of claim 21, wherein said chemotherapy comprises cisplatin. 38. The method of claim 21, wherein said chemotherapy comprises carboplatin, cisplatin, oxaliplatin, or doxorubicin. 39. The method of claim 21, wherein said chemotherapy comprises cyclophosphamide. 40. The method of claim 2, wherein said treatment of CINV is defined as no emetic episodes and no use of rescue medication following said chemotherapy. 41. The method of claim 2, wherein: a) said regimen comprises a single administration of netupitant or pharmaceutically acceptable salt thereof, without administering a second dose for at least five days after said chemotherapy; b) said chemotherapy comprises moderately emetogenic or highly emetogenic chemotherapy; c) if said chemotherapy comprises moderately emetogenic chemotherapy, said regimen comprises a single administration of dexamethasone without administering a second dose for at least five days after said chemotherapy; d) if said chemotherapy comprises highly emetogenic chemotherapy, said regimen comprises administering a first dose of dexamethasone on day one and a second dose of dexamethasone on two, three and four after said chemotherapy; e) said netupitant or pharmaceutically acceptable salt thereof and said first dose of dexamethasone are administered prior to said chemotherapy; f) said regimen is effective to treat said CINV for a five day period after said chemotherapy. 42. The method of claim 2, wherein: a) said treatment of CINV is defined as no emetic episodes and no use of rescue medication following said chemotherapy; b) said regimen comprises a single administration of netupitant or pharmaceutically acceptable salt thereof, without administering a second dose for at least five days after said chemotherapy; c) said chemotherapy comprises moderately emetogenic or highly emetogenic chemotherapy; d) if said chemotherapy comprises moderately emetogenic chemotherapy, said regimen comprises a single administration of dexamethasone without administering a second dose for at least five days after said chemotherapy; e) if said chemotherapy comprises highly emetogenic chemotherapy, said regimen comprises administering a first dose of dexamethasone on day one and a second dose of dexamethasone on two, three and four after said chemotherapy; f) said netupitant or pharmaceutically acceptable salt thereof and said first dose of dexamethasone are administered prior to said chemotherapy; g) said regimen is effective to treat said CINV for a five day period after said chemotherapy. 43. The method of claim 35, wherein: a) said chemotherapy comprises moderately emetogenic chemotherapy; b) said netupitant is administered orally as the free base in a dose of about 300 mg less than 2 hours prior to said chemotherapy; and c) said single administration of dexamethasone comprises about 12 mg, in a dosage form independent of said netupitant less than 2 hours prior to said chemotherapy. 44. The method of claim 35, wherein: a) said chemotherapy comprises highly emetogenic chemotherapy; b) said netupitant is administered orally as the free base in a dose of about 300 mg less than 2 hours prior to said chemotherapy; c) said first dose of dexamethasone comprises about 12 mg, in a dosage form independent of said netupitant, administered less than 2 hours prior to said chemotherapy; and d) said second dose comprises about 8 mg of dexamethasone administered on days 2, 3 and 4 following said chemotherapy. 45. The method of claim 35, wherein said netupitant occupies at least 70% of said patient's striatum NK1 receptors ninety-six hours after said administration. 46. The method of claim 35, wherein said netupitant is effective to treat said CINV during the acute and delayed phases of said CINV. 47. The method of claim 35, wherein said regimen is effective to prevent nausea in said patient following the administration of said chemotherapy. 48. The method of claim 35, wherein said regimen is effective to reduce the severity of nausea in said patient following the administration of said chemotherapy. 49. The method of claim 35, wherein said chemotherapy comprises cisplatin. 50. The method of claim 35, wherein said chemotherapy comprises carboplatin, cisplatin, oxaliplatin, or doxorubicin. 51. The method of claim 35, wherein said chemotherapy comprises cyclophosphamide. 52. The method of claim 4, wherein said treatment of CINV is defined as no emetic episodes and no use of rescue medication following said chemotherapy. 53. The method of claim 4, wherein: a) said blood levels are induced by an intravenous anti-emetic regimen administered prior to said chemotherapy; and b) said regimen is effective to treat said CINV for a five day period after said chemotherapy. 54. The method of claim 4, wherein: a) said treatment of CINV is defined as no emetic episodes and no use of rescue medication following said chemotherapy b) said blood levels are induced by an intravenous anti-emetic regimen administered prior to said chemotherapy; and c) said regimen is effective to treat said CINV for a five day period after said chemotherapy. 55. The method of claim 54, wherein said netupitant occupies at least 70% of said patient's striatum NK1 receptors ninety-six hours after said administration. 56. The method of claim 54, wherein said chemotherapy is highly emetogenic chemotherapy, said netupitant blood levels are effective to treat said CINV during the acute and delayed phases of said CINV, and said palonosetron blood levels are effective to treat said CINV during the acute phase of said CINV. 57. The method of claim 54, wherein said chemotherapy is moderately emetogenic chemotherapy, said netupitant blood levels are effective to treat said CINV during the acute and delayed phases of said CINV, and said palonosetron blood levels are effective to treat said CINV during the acute phase of said CINV. 58. The method of claim 54, wherein said chemotherapy is highly emetogenic chemotherapy, and said regimen is effective to prevent or reduce the severity of nausea during the acute and delayed phases. 59. The method of claim 54, wherein said chemotherapy is moderately emetogenic chemotherapy, and said regimen is effective to prevent or reduce the severity of nausea during the acute and delayed phases. 60. The method of claim 54, wherein said chemotherapy comprises cisplatin. 61. The method of claim 54, wherein said chemotherapy comprises carboplatin, cisplatin, oxaliplatin, or doxorubicin. 62. The method of claim 54, wherein said chemotherapy comprises cyclophosphamide.