Compositions, devices, and methods for treating or preventing headaches

1. A method of treatment or prevention of a headache, comprising administering to a human subject a powdery pharmaceutical composition that comprises an active agent, wherein said active agent is present in 4.5 mg to about 6 mg in a unit dose of said pharmaceutical composition and is selected from the group consisting of a compound having a formula of

a pharmaceutically acceptable salt thereof, a complex thereof, a chelate thereof, and an ion pair thereof, wherein R 12 is hydrogen or halogen in said formula,

wherein said administering results in a time to reach a peak plasma concentration (T max ) of 90 minutes or longer for a metabolite of said active agent, when determined from measurement of a human plasma concentration of said metabolite by liquid chromatography-tandem mass spectrometry with automated extraction, wherein said metabolite is of Formula (I) in which R 12 is —OH, and

wherein:

R 1 is hydrogen, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) perfluoroalkyl;

each R 2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO 2 , —N 3 , —OH, —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , or —CO 2 R 106 ;

R 3 and R 4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

R 5 , R 6 , and R 7 are independently hydrogen, (C 1 -C 3 ) alkyl, or (C 1 -C 3 ) perfluoroalkyl;

R 8 and R 9 are independently hydrogen, (C 1 -C 4 ) alkyl, or benzyl;

R 10 , R 11 , and R 14 are independently hydrogen, halogen, —OH, (C 1 -C 4 ) alkyl, —CO 2 R 108 , or —CONR 109 R 110 ;

R 13 is hydrogen or halogen;

R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 108 , R 109 , and R 110 are independently hydrogen, halogen, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;

and

n is 0, 1, 2, or 3.

2. The method of claim 1 , wherein said T max is at least about 2 hours.

3. The method of claim 1 , wherein a peak plasma concentration (C max ) of said metabolite is less than about 250 pg/ml.

4. The method of claim 1 , wherein a peak plasma concentration (C max ) of said metabolite is less than about 15% of a C max of said active agent measured following said administration to said human subject.

5. The method of claim 1 , wherein a plasma concentration of said metabolite is less than about 5% of a plasma concentration of said active agent measured within about 30 minutes following said administration to said human subject, or wherein a plasma concentration of said metabolite is less than about 2% of a plasma concentration of said active agent measured within about 15 minutes following said administration to said human subject.

6. The method of claim 1 , wherein a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect is less than 20% binding activity at an adrenergic, dopaminergic, or 5-HT receptor or receptor subtype as measured by a radioligand competitive binding assay.

7. The method of claim 1 , wherein a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect in said human subject is manifested by a reduced transcutaneous partial O 2 pressure as measured at the back of a foot, a reduced venous constrictive effect as determined using a venous occlusion mercury strain gauge, a less decreased diameter or compliance of a brachial artery wall, a decreased constrictive effect on a human coronary artery, meningeal artery, or saphenous vein, a less decreased venous diameter at a fixed occlusion pressure, a change in peripheral circulatory capacitance, or any combination thereof.

8. A method of treatment or prevention of a headache, comprising administering to a human subject a pharmaceutical composition that comprises an active agent, wherein said active agent is present in 4.5 mg to about 6 mg in a unit dose of said pharmaceutical composition and is selected from the group consisting of a compound having a formula of

a pharmaceutically acceptable salt thereof, a complex thereof, a chelate thereof, and an ion pair thereof,

wherein said administering results in:

1) a C max of about 1 to about 2.5 ng/ml, or a plasma concentration of at least 1 ng/mL at about 10 minutes or shorter,

2) a T max of about 30 minutes or less, and

3) an AUC value selected from the group consisting of an AUC 0-30min of about 500 to about 1000 h*pg/ml, an AUC 0-60min of about 1000 to about 2000 h*pg/ml, an AUC 0-120min of about 2000 to about 3000 h*pg/ml, and an AUC 0-inf of about 10000 to about 12000 h*pg/ml,

when determined from measurement of a human plasma concentration of said active agent by liquid chromatography-tandem mass spectrometry with automated extraction, and

wherein:

R 1 is hydrogen, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) perfluoroalkyl;

each R 2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO 2 , —N 3 , —OH, —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , or —CO 2 R 106 ;

R 3 and R 4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

R 5 , R 6 , and R 7 are independently hydrogen, (C 1 -C 3 ) alkyl, or (C 1 -C 3 ) perfluoroalkyl;

R 8 and R 9 are independently hydrogen, (C 1 -C 4 ) alkyl, or benzyl;

R 10 , R 11 , R 12 , and R 14 are independently hydrogen, halogen, —OH, (C 1 -C 4 ) alkyl, —CO 2 R 108 , or —CONR 109 R 110 ;

R 13 is hydrogen or halogen;

R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 108 , R 109 , and R 110 are independently hydrogen, halogen, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;

and

n is 0, 1, 2, or 3.

9. The method of claim 8 , further providing a half-life of said active agent from about 12 hours to about 13 hours.

10. The method of claim 8 , wherein said administering results in a time to reach a peak plasma concentration (T max ) of 90 minutes or longer for a metabolite of said active agent, when determined from measurement of a human plasma concentration of said metabolite by liquid chromatography-tandem mass spectrometry with automated extraction, wherein R 12 is hydrogen or halogen in said formula of said active agent, and wherein said metabolite is of Formula (I) in which R 12 is —OH.

11. A method of treatment or prevention of a headache, comprising administering to a human subject a pharmaceutical composition that comprises an active agent, wherein said active agent is present in 4.5 mg to about 6 mg in a unit dose of said pharmaceutical composition and is selected from the group consisting of a compound having a formula of

a pharmaceutically acceptable salt thereof, a complex thereof, a chelate thereof, and an ion pair thereof,

wherein said administering results in an apparent clearance (CL/F) value of said active agent from about 100 L/hr to about 1000 L/hr, and

wherein:

R 1 is hydrogen, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) perfluoroalkyl;

each R 2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO 2 , —N 3 , —OH, —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , or —CO 2 R 106 ;

R 3 and R 4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

R 5 , R 6 , and R 7 are independently hydrogen, (C 1 -C 3 ) alkyl, or (C 1 -C 3 ) perfluoroalkyl;

R 8 and R 9 are independently hydrogen, (C 1 -C 4 ) alkyl, or benzyl;

R 10 , R 11 , R 12 , and R 14 are independently hydrogen, halogen, —OH, (C 1 -C 4 ) alkyl, —CO 2 R 108 , or —CONR 109 R 110 ;

R 13 is hydrogen or halogen;

R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 108 , R 109 , and R 110 are independently hydrogen, halogen, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;

and

n is 0, 1, 2, or 3.

12. The method of claim 1 , wherein said R 3 and said R 4 are both hydrogen.

13. The method of claim 12 , wherein said active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein said metabolite is 8′-hydroxy dihydroergotamine.

15. The method of claim 1 , wherein said pharmaceutical composition further comprises about 6 mg to about 7 mg of a sugar alcohol.

16. The method of claim 1 , wherein said active agent is in an amorphous form.

17. The method of claim 1 , wherein said headache is a migraine.

18. The method of claim 1 , wherein said headache comprises a migraine headache with aura, a migraine headache without aura, cluster headache, post-traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, refractory migraine, migraine attack when treatment is initiated at least 1-24 hours after an onset of attack, migraine attack when treatment is initiated at the earliest premonitory sign or symptom, pediatric migraine, status migraine, chronic daily headache, a migraine attack with allodynia, menstrually-associated migraine, menstrual migraine, migraine-upon-awakening, rapid-onset migraine, or any combination thereof.

19. The method of claim 1 , wherein said administration comprises delivering two or more doses of said pharmaceutical composition in two or more devices to said human subject.

20. The method of claim 19 , wherein a first dose and a second dose of said two or more doses are separated by about 2 hours or longer.

21. The method of claim 1 , wherein said pharmaceutical composition further comprises a carrier that is at least partially adhesive to mucus.

22. The method of claim 1 , wherein said pharmaceutical composition further comprises a carrier, and wherein the carrier is at least partially adhesive to mucus and present in an amount at least partially effective to result in said Tmax.

23. The method of claim 1 , wherein said pharmaceutical composition further comprises a carrier, and wherein the carrier is at least partially adhesive to mucus and present in at least 12 mg in a unit dose of said pharmaceutical composition.

24. The method of claim 1 , wherein said administering comprises delivering said pharmaceutical composition in a delivery device that comprises a poppet valve and a retainer that holds the poppet valve.

25. The method of claim 1 , wherein said active agent comprises a pharmaceutically acceptable salt of dihydroergotamine.

26. The method of claim 1 , wherein said active agent comprises dihydroergotamine mesylate.

27. The method of claim 26 , wherein at least one of the following applies:

said T max is at least about 2 hours;

a peak plasma concentration (C max ) of said metabolite is less than about 250 pg/ml;

a peak plasma concentration (C max ) of said metabolite is less than about 15% of a C max of said active agent measured following said administration to said human subject;

a plasma concentration of said metabolite is less than about 5% of a plasma concentration of said active agent measured within about 30 minutes following said administration to said human subject, or wherein a plasma concentration of said metabolite is less than about 2% of a plasma concentration of said active agent measured within about 15 minutes following said administration to said human subject;

a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect is less than 20% binding activity at an adrenergic, dopaminergic, or 5-HT receptor or receptor subtype as measured by a radioligand competitive binding assay; or

a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect in said human subject is manifested by a reduced transcutaneous partial O 2 pressure as measured at the back of a foot, a reduced venous constrictive effect as determined using a venous occlusion mercury strain gauge, a less decreased diameter or compliance of a brachial artery wall, a decreased constrictive effect on a human coronary artery, meningeal artery, or saphenous vein, a less decreased venous diameter at a fixed occlusion pressure, a change in peripheral circulatory capacitance, or any combination thereof.

28. The method of claim 8 , wherein said active agent comprises dihydroergotamine mesylate.

29. The method of claim 28 , further providing a half-life of said active agent from about 12 hours to about 13 hours, or wherein said administering results in a time to reach a peak plasma concentration (T max ) of 90 minutes or longer for a metabolite of said active agent, when determined from measurement of a human plasma concentration of said metabolite by liquid chromatography-tandem mass spectrometry with automated extraction, wherein R 12 is hydrogen or halogen in said formula of said active agent, and wherein said metabolite is of Formula (I) in which R 12 is —OH.

30. The method of claim 11 , wherein said active agent comprises dihydroergotamine mesylate.

31. The method of claim 1 , wherein said active agent is dihydroergotamine mesylate, and wherein said metabolite comprise 8′-hydroxy dihydroergotamine.

32. The method of claim 1 , wherein said T max is a mean value from a human clinical study.

33. The method of claim 2 , wherein said T max is a mean value from a human clinical study.

34. The method of claim 8 , wherein said C max , T max and AUC value are mean values from a human clinical study.

35. The method of claim 11 , wherein said CL/F value is a mean value from a human clinical study.