Hydroxybupropion and related compounds as modulators of drug plasma levels

• US 9,486,450 B2
• Filed: 02/09/2015
• Issued: 11/08/2016
• 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): BARSKY, JARED
• Application Number:
  US14/617,624
• Publication Number:
  US 20150150830A1
• Time in Patent Office: 638 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• 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
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031

Abstract

This disclosure relates to methods administering hydroxybupropion or a prodrug thereof in conjunction with dextromethorphan to a human being. Dosage forms, drug delivery systems, and methods related to dextromethorphan or dextrorphan and hydroxybupropion or a prodrug of hydroxybupropion are also disclosed.

Claims

1. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering a) a hydroxybupropion or a bupropion with b) a dextromethorphan at least daily to the human being for at least eight consecutive days,

wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan,

wherein the hydroxybupropion or the bupropion and the dextromethorphan are the sole active agents administered to the human being,

wherein the hydroxybupropion or the bupropion is administered in an amount that results in an AUC_0-12 of the dextromethorphan that is at least about 40 ng·

hr/mL, and

wherein, on the eighth day that the hydroxybupropion or the bupropion and the dextromethorphan are co-administered, the AUC_0-12 of the dextromethorphan is at least about 20 times the AUC_0-12 of the dextromethorphan that would result from administering the same amount of the dextromethorphan without the hydroxybupropion or the bupropion.

2. The method of claim 1, wherein the AUC_0-12 of the dextromethorphan on the eighth day is at least about 50 ng·

hr/mL.

3. The method of claim 1, wherein the AUC_0-12 of the dextromethorphan on the eighth day is at least about 100 ng·

hr/mL.

4. The method of claim 1, wherein the AUC_0-12 of the dextromethorphan on the eighth day is at least about 400 ng·

hr/mL.

5. The method of claim 1, wherein the AUC_0-12 of the dextromethorphan on the eighth day is at least about 700 ng·

hr/mL.

6. The method of claim 1, wherein the AUC_0-24 of the dextromethorphan on the eighth day is at least about 100 ng·

hr/mL.

7. The method of claim 1, wherein the AUC_0-24 of the dextromethorphan on the eighth day is at least about 1000 ng·

hr/mL.

8. The method of claim 1, wherein the AUC_0-inf of the dextromethorphan on the eighth day is at least about 2000 ng·

hr/mL.

9. The method of claim 1, wherein the AUC_0-inf of the dextromethorphan on the eighth day is at least about 3000 ng·

hr/mL.

18. The method of claim 1, wherein the human being is at risk of experiencing an adverse event as a result of being treated with the bupropion and the risk of the human being experiencing an adverse event is reduced by the co-administration of the dextromethorphan.

19. The method of claim 1, wherein the hydroxybupropion or the bupropion and the dextromethorphan are co-administered for at least thirty days.

20. The method of claim 1, wherein the hydroxybupropion or the bupropion and the dextromethorphan are independently administered either orally or parenterally.

21. The method of claim 20, wherein the hydroxybupropion or the bupropion is orally administered in a solid dosage form.

22. The method of claim 20, wherein the dextromethorphan is orally administered in a solid dosage form.

10. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering a) a hydroxybupropion or a bupropion with b) a dextromethorphan to the human being,

wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan,

wherein the hydroxybupropion or the bupropion and the dextromethorphan are the sole active agents administered to the human being,

wherein the hydroxybupropion or the bupropion is administered at least daily for at least eight consecutive days in an amount that results in a C_max of the dextromethorphan that is at least about 6 ng/mL, and

wherein, on the eighth day that the hydroxybupropion or the bupropion and the dextromethorphan are co-administered, the AUC_0-12 of the dextromethorphan is at least about 20 times the AUC_0-12 of the dextromethorphan that would result from administering the same amount of the dextromethorphan without the hydroxybupropion or the bupropion.

11. The method of claim 10, wherein the C_max of the dextromethorphan on the eighth day is at least about 10 ng/mL.

12. The method of claim 10, wherein the C_max of the dextromethorphan on the eighth day is at least about 60 ng/mL.

13. The method of claim 10, wherein the C_max of the dextromethorphan on the eighth day is at least about 80 ng/mL.

23. The method of claim 10, wherein the hydroxybupropion or the bupropion and the dextromethorphan are independently administered either orally or parenterally.

24. The method of claim 23, wherein the hydroxybupropion or the bupropion is orally administered in a solid dosage form.

25. The method of claim 23, wherein the dextromethorphan is orally administered in a solid dosage form.

14. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering at least daily for at least eight consecutive days a) a hydroxybupropion or a bupropion with b) a dextromethorphan to the human being,

wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan,

wherein the hydroxybupropion or the bupropion and the dextromethorphan are the sole active agents administered to the human being,

wherein the hydroxybupropion or the bupropion is administered in an amount that results in a C_avg of the dextromethorphan, over the period between two separate and consecutive administrations of the dextromethorphan, that is at least about 5 ng/mL, and

wherein, on the eighth day that the hydroxybupropion or the bupropion and the dextromethorphan are co-administered, the AUC_0-12 of the dextromethorphan is at least about 20 times the AUC_0-12 of the dextromethorphan that would result from administering the same amount of the dextromethorphan without the hydroxybupropion or the bupropion.

15. The method of claim 14, wherein the hydroxybupropion or the bupropion is administered in an amount that results in a C_avg of the dextromethorphan, over the period between two separate and consecutive administrations of the dextromethorphan, that is at least about 60 ng/mL.

16. The method of claim 14, wherein the C_avg of the dextromethorphan on the eighth day is at least about 8 ng/mL,

wherein the C_avg is for the period between two separate and consecutive administrations of the dextromethorphan, or

if the dextromethorphan is administered only once on the eighth day, the C_avg is for the period of twelve hours from the only dose of the dextromethorphan on the eighth day.

17. The method of claim 14, wherein the C_avg of the dextromethorphan on the eighth day is at least about 30 ng/mL,

wherein the C_avg is for the period between two separate and consecutive administrations of the dextromethorphan, or

if the dextromethorphan is administered only once on the eighth day, the C_avg is for the period of twelve hours from the only dose of the dextromethorphan on the eighth day.

26. The method of claim 14, wherein the hydroxybupropion or the bupropion and the dextromethorphan are independently administered either orally or parenterally.

27. The method of claim 26, wherein the hydroxybupropion or the bupropion is orally administered in a solid dosage form.

28. The method of claim 26, wherein the dextromethorphan is orally administered in a solid dosage form.

29. The method of claim 14, wherein the plasma level of hydroxybupropion is about 0.1 μ

M to about 10 μ

M.

30. The method of claim 14, wherein the hydroxybupropion or the bupropion and the dextromethorphan are co-administered in a single dosage form.