Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects

• US 9,370,513 B2
• Filed: 12/22/2015
• Issued: 06/21/2016
• Est. Priority Date: 11/05/2013
• Status: Active Grant

• Current Assignee: Antecip Bioventures II LLC
• Original Assignee: Antecip Bioventures II LLC
• Inventors: Tabuteau, Herriot
• Primary Examiner(s): Baek, Bong-Sook
• Application Number:
  US14/978,976
• Publication Number:
  US 20160136155A1
• Time in Patent Office: 182 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4748 forming part of bridged ring systems strychnine A61K31/475; morphinan derivatives A61K31/485
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine

Abstract

This disclosure relates to methods of increasing the metabolic lifetime of dextromethorphan administering threohydroxybupropion or bupropion to a human being. Dosage forms, drug delivery systems, and methods related to dextromethorphan or dextrorphan and threohydroxybupropion or bupropion are also disclosed.

Claims

1. A method of increasing the metabolic lifetime of dextromethorphan, comprising co-administering threohydroxybupropion or bupropion with dextromethorphan to a human being once or twice a day for at least eight consecutive days, wherein threohydroxybupropion or bupropion is administered in an amount that results in an AUC_0-12 of threohydroxybupropion in the human being, on the eighth day, that is at least about 1,000 ng·

hr/mL, wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, wherein the co-administration results in an AUC_0-12 of dextromethorphan that, on the eighth day, is at least about 20 times the AUC_0-12 that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion for eight consecutive days, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion or bupropion.

2. The method of claim 1, wherein an increase in the dextromethorphan plasma level occurs on the first day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or bupropion.

3. The method of claim 2, wherein the dextromethorphan plasma level on the first day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, is at least twice the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion.

4. The method of claim 1, wherein, on the fifth day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion for five consecutive days.

5. The method of claim 4, wherein the dextromethorphan plasma level, on the fifth day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, is at least 20 times the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion for five consecutive days.

6. The method of claim 1, wherein, on the sixth day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion for six consecutive days.

7. The method of claim 6, wherein the dextromethorphan plasma level, on the sixth day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, is at least 30 times the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion for six consecutive days.

8. The method of claim 1, wherein, after the first co-administration of threohydroxybupropion or bupropion with dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or bupropion with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion.

9. The method of claim 1, wherein, on the fifth day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or bupropion with dextromethorphan that is at least 40 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion.

10. The method of claim 1, wherein, on the sixth day that threohydroxybupropion or bupropion are co-administered, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or bupropion with dextromethorphan that is at least 50 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion.

11. The method of claim 1, wherein, on the seventh day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or bupropion with dextromethorphan that is at least 70 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion.

12. The method of claim 1, wherein, on the eighth day that threohydroxybupropion or bupropion and dextromethorphan are co-administered, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or bupropion with dextromethorphan that is at least 80 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion.

13. The method of claim 1, wherein threohydroxybupropion, bupropion, or dextromethorphan is deuterium-modified.

14. The method of claim 13, wherein dextromethorphan is deuterium-modified.

15. A method of administering dextromethorphan twice a day without loss of efficacy, comprising orally co-administering threohydroxybupropion or bupropion with dextromethorphan to a human being twice a day for at least eight consecutive days, wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, wherein threohydroxybupropion or bupropion is administered in an amount that results in an AUC_0-12 of threohydroxybupropion in the human being, on the eight day that is at least about 2,000 ng·

hr/mL, wherein the co-administration results in an AUC_0-12 of dextromethorphan that, on the eighth day, is at least about 20 times the AUC_0-12 that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion for eight consecutive days.

16. The method of claim 15, wherein the treatment is at least as effective as administering the same amount of dextromethorphan four times a day without administering threohydroxybupropion or bupropion.

17. The method of claim 15, wherein the treatment is at least as effective as administering the same amount of dextromethorphan three times a day without administering threohydroxybupropion or bupropion.

18. The method of claim 15, wherein about 35 mg to about 120 mg of dextromethorphan is administered per day.

19. The method of claim 15, wherein the threohydroxybupropion, bupropion, or dextromethorphan is deuterium-modified.

20. The method of claim 19, wherein the dextromethorphan is deuterium-modified.

21. A method of increasing the metabolic lifetime of dextromethorphan, comprising co-administering threohydroxybupropion or bupropion with dextromethorphan to a human being once a day for at least eight consecutive days, wherein threohydroxybupropion or bupropion is administered in an amount that results in an AUC_0-12 of threohydroxybupropion in the human being, on the eighth day, that is at least about 1,000 ng·

hr/mL, wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, wherein the co-administration results in an AUC_0-12 of dextromethorphan that, on the eighth day, is at least about 30 times the AUC_0-12 that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or bupropion for eight consecutive days, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion or bupropion.

22. The method of claim 21, wherein dextromethorphan, bupropion, or threohydroxybupropion is deuterium-modified.

23. The method of claim 22, wherein the dextromethorphan is deuterium-modified.

24. The method of claim 21, wherein dextromethorphan, and bupropion or threohydroxybupropion are orally administered.

25. The method of claim 24, wherein dextromethorphan, and bupropion or threohydroxybupropion are orally administered in a solid dosage form.

26. The method of claim 25, wherein the solid dosage form comprises at least about 5% (w/w) dextromethorphan.

27. The method of claim 21, wherein the plasma level of threohydroxybupropion in the human being is about 0.1 μ

M to about 10 μ

M.

28. The method of claim 21, wherein about 20 mg to about 70 mg of dextromethorphan and about 50 mg to about 150 mg bupropion are administered per dose.