Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
This disclosure relates to methods administering various compounds in conjunction with dextromethorphan to a human being. Dosage forms, drug delivery systems, and methods related to dextromethorphan or dextrorphan and bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds are also disclosed.
1. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering a bupropion, a hydroxybupropion, a threohydroxybupropion, or an erythrohydroxybupropion with a dextromethorphan 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 bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are the sole active agents administered to the human being, wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion is administered in an amount that results in an AUC 0-24 of dextromethorphan that is at least about 50 ng·hr/mL, and wherein, on the eighth day that the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are co-administered, the AUC 0-12 of dextromethorphan is at least about 20 times the AUC 0-12 of dextromethorphan that would result from administering the same amount of the dextromethorphan without the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion.
2. The method of claim 1 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are administered in a single dosage form.
3. The method of claim 2 , wherein about 10 mg to about 300 mg of the dextromethorphan is administered.
4. The method of claim 2 , wherein about 10 mg to about 600 mg of the bupropion is administered.
5. The method of claim 1 , wherein the AUC 0-24 of dextromethorphan on the eighth day is at least about 100 ng·hr/mL.
6. The method of claim 1 , wherein the AUC 0-24 of dextromethorphan on the eighth day is at least about 200 ng·hr/mL.
7. The method of claim 1 , wherein the AUC 0-24 of dextromethorphan on the eighth day is at least about 400 ng·hr/mL.
8. The method of claim 1 , wherein the AUC 0-24 of dextromethorphan on the eighth day is at least about 700 ng·hr/mL.
9. The method of claim 1 , wherein the AUC 0-24 of dextromethorphan on the eighth day is at least about 1000 ng·hr/mL.
10. The method of claim 1 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion are co-administered with the dextromethorphan for at least nine consecutive days.
11. The method of claim 1 , wherein the fluctuation index value (FI(%)) of dextromethorphan is reduced by at least 1.50 fold as compared to dextromethorphan that is administered for eight days without co-administration with the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion.
12. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering a bupropion, a hydroxybupropion, a threohydroxybupropion, or an erythrohydroxybupropion with a dextromethorphan 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 bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are the sole active agents administered to the human being, wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion is administered in an amount that results in a C min of dextromethorphan that is at least about 10 ng/mL, and wherein, on the eighth day that the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are co-administered, the AUC 0-12 of dextromethorphan is at least about 50 times the AUC 0-12 of dextromethorphan that would result from administering the same amount of dextromethorphan without the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion.
13. The method of claim 12 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are co-administered for at least 30 days.
14. The method of claim 12 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are co-administered for at least 60 days.
15. The method of claim 12 , wherein the C min of dextromethorphan on the eighth day is at least about 20 ng/mL.
16. The method of claim 13 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion is administered in an amount that results in a C min of dextromethorphan that, on the ninth day, is at least about 20 ng/mL.
17. The method of claim 13 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion is administered in an amount that results in a C min of dextromethorphan that, on the tenth day, is at least about 20 ng/mL.
18. The method of claim 12 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are administered in a single dosage form.
19. The method of claim 12 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are administered at least twice a day.
20. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering a bupropion, a hydroxybupropion, a threohydroxybupropion, or an erythrohydroxybupropion with a dextromethorphan 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 bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are the sole active agents administered to the human being, wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion is administered in an amount that results in a C avg of dextromethorphan, over a period between two separate and consecutive administrations of the dextromethorphan, that is at least about 8 ng/mL, and wherein, on the eighth day that the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are co-administered, the AUC 0-12 of dextromethorphan is at least about 20 times the AUC 0-12 of dextromethorphan that would result from administering the same amount of dextromethorphan without the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion.
21. The method of claim 20 , wherein the dextromethorphan is deuterium-modified.
22. The method of claim 20 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are administered for at least 30 consecutive days, and the C avg of dextromethorphan on the eighth day is at least about 15 ng/mL for the period between two separate and consecutive administrations of the dextromethorphan.
23. The method of claim 20 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are administered for at least 30 consecutive days, and the C avg of dextromethorphan on the eighth day is at least about 25 ng/mL for the period between two separate and consecutive administrations of the dextromethorphan.
24. The method of claim 20 , wherein the FI(%) of dextromethorphan is reduced by at least 2-fold as compared to dextromethorphan that is administered for eight days without co-administration with the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion.
25. The method of claim 20 , wherein the FI(%) of dextromethorphan is less than 100%.
26. The method of claim 20 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are administered orally.
27. The method of claim 20 , wherein the bupropion is administered, and contains an excess of an R-enantiomer of bupropion or an S-enantiomer of bupropion.
28. The method of claim 20 , wherein the dextromethorphan is administered in a solid dosage form containing about 10 mg to about 700 mg of the dextromethorphan.
29. The method of claim 20 , wherein about 10 mg to about 600 mg of the bupropion is administered in a solid dosage form.