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 enhancing dextromethorphan plasma levels in a human being, comprising co-administering a bupropion, a hydroxybupropion, a threohydroxybupropion, or a 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 max of dextromethorphan that is at least about 35 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 C max of dextromethorphan is at least about 15 times the C max 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 orally administered.
3. The method of claim 2 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, are orally administered in a single, solid dosage form.
4. The method of claim 1 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion is in a form that contains an enantiomeric excess of the S-enantiomer.
5. The method of claim 1 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion is in a form that contains an enantiomeric excess of the R-enantiomer.
6. The method of claim 1 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, the erythrohydroxybupropion, or the dextromethorphan is deuterium-modified.
7. The method of claim 6 , wherein the dextromethorphan is deuterium-modified.
8. The method of claim 1 , wherein the C max of dextromethorphan on the eighth day is at least about 50 ng/mL.
9. The method of claim 1 , wherein the C max of dextromethorphan on the eighth day is at least about 60 ng/mL.
10. The method of claim 1 , wherein the C max of dextromethorphan on the eighth day is at least about 70 ng/mL.
11. The method of claim 1 , wherein the C max of dextromethorphan is at least about 20 times the C max of dextromethorphan that would result from administering the same amount of the dextromethorphan without the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion.
12. The method of claim 1 , wherein a C min of dextromethorphan on the eighth day is at least about 20 ng/mL.
13. The method of claim 1 , wherein the human being is at least 50 years of age.
14. The method of claim 1 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion are co-administered with the dextromethorphan for at least 14 consecutive days.
15. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering a bupropion, a hydroxybupropion, a threohydroxybupropion, or a 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 20 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 C max of dextromethorphan is at least about 15 times the C max of dextromethorphan that would result from administering the same amount of dextromethorphan without the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion.
16. The method of claim 15 , wherein about 30 mg to about 50 mg of the dextromethorphan is administered to the human being twice a day.
17. The method of claim 16 , wherein about 105 mg to about 110 mg of the bupropion is administered to the human being twice a day.
18. The method of claim 15 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion are co-administered with the dextromethorphan for at least 30 consecutive days.
19. The method of claim 15 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, and the dextromethorphan, is 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 a 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 the period between two separate and consecutive administrations of the dextromethorphan, that is at least about 25 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 C max of dextromethorphan is at least about 20 times the C max 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 human being is about 30 to about 50 years of age.
22. The method of claim 20 , wherein the bupropion, the hydroxybupropion, the threohydroxybupropion, or the erythrohydroxybupropion, are co-administered with the dextromethorphan for at least 30 consecutive days.
23. The method of claim 20 , wherein the C max of dextromethorphan on the eighth day is at least about 45 ng/mL.
24. The method of claim 20 , wherein the dextromethorphan is administered in a dosage form that is immediate release for dextromethorphan.
25. The method of claim 20 , wherein the bupropion is co-administered with the dextromethorphan, and the weight ratio of the dextromethorphan to the bupropion is about 0.4 to about 0.45.
26. The method of claim 20 , wherein the fluctuation index value FI (%) of the 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.
27. The method of claim 20 , wherein the FI (%) of the dextromethorphan is less than 100%.
28. The method of claim 20 , wherein about 44 mg to about 46 mg of the dextromethorphan is administered twice a day.
29. The method of claim 20 , where about 15 mg to about 140 mg of the dextromethorphan is administered daily.