Compositions and Methods for Increasing the Metabolic Lifetime of Dextromethorphan and Related Pharmacodynamic Effects

1 . A method of increasing the metabolic lifetime of dextromethorphan, comprising administering threohydroxybupropion or a prodrug thereof to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion.

2 . The method of claim 1 , wherein the threohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of co-administration of threohydroxybupropion or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that threohydroxybupropion or a prodrug thereof and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.

3 . The method of claim 2 , wherein the dextromethorphan plasma level on the first day that threohydroxybupropion or a prodrug thereof 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 a prodrug thereof.

4 . The method of claim 1 , comprising co-administering threohydroxybupropion or a prodrug thereof and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, 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 a prodrug thereof for five consecutive days.

5 . The method of claim 4 , wherein the dextromethorphan plasma level, on the fifth day that threohydroxybupropion or a prodrug thereof 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 a prodrug thereof for five consecutive days.

6 . The method of claim 1 , comprising co-administering threohydroxybupropion or a prodrug thereof and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, 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 a prodrug thereof for six consecutive days.

7 . The method of claim 6 , wherein the dextromethorphan plasma level, on the sixth day that threohydroxybupropion or a prodrug thereof 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 a prodrug thereof for six consecutive days.

8 . The method of claim 1 , comprising co-administering threohydroxybupropion or a prodrug thereof with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

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

10 . The method of claim 1 , wherein threohydroxybupropion or a prodrug thereof is co-administered with dextromethorphan for at least five consecutive days, wherein, on the fifth day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or a prodrug thereof 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 a prodrug thereof.

11 . The method of claim 1 , wherein threohydroxybupropion or a prodrug thereof is co-administered with dextromethorphan for at least six consecutive days, wherein, on the sixth day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or a prodrug thereof 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 a prodrug thereof.

12 . The method of claim 1 , wherein threohydroxybupropion or a prodrug thereof is co-administered with dextromethorphan for at least seven consecutive days, wherein, on the seventh day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or a prodrug thereof 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 a prodrug thereof.

13 . The method of claim 1 , wherein threohydroxybupropion or a prodrug thereof is co-administered with dextromethorphan for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion or a prodrug thereof 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 a prodrug thereof.

14 . The method of claim 1 , comprising co-administering threohydroxybupropion or a prodrug thereof and dextromethorphan to a human being in need of dextromethorphan treatment, wherein the human being is at risk of experiencing an adverse event as a result of being treated with dextromethorphan, thereby reducing the adverse event.

15 . The method claim 1 , wherein dextromethorphan is administered to the human being at least daily for at least 8 days.

16 . The method of claim 15 , wherein threohydroxybupropion or a prodrug thereof is administered in an amount that results in an AUC 0-12 of threohydroxybupropion, on day 8, that is at least about 2000 ng·hr/mL.

17 . A method of decreasing dextrorphan plasma levels comprising co-administering:

threohydroxybupropion or a prodrug thereof, and

dextromethorphan

to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that threohydroxybupropion or a prodrug thereof and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.

18 . The method of claim 17 , wherein the dextrorphan plasma level, on the first day that threohydroxybupropion or a prodrug thereof and dextromethorphan are co-administered, is reduced by at least 5%, as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

19 . The method of claim 17 , comprising co-administering threohydroxybupropion or a prodrug thereof and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof for eight consecutive days.

20 . The method of claim 19 , wherein the dextrorphan plasma level on the eighth day that threohydroxybupropion or a prodrug thereof and dextromethorphan are co-administered is reduced by at least 30%, as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof for eight consecutive days.

21 . An oral sustained release delivery system for dextromethorphan, comprising:

threohydroxybupropion or a prodrug thereof,

dextromethorphan, and

a water soluble excipient.

22 . The oral sustained release delivery system of claim 21 , comprising about 35 mg to about 70 mg of dextromethorphan.

23 . The oral sustained release delivery system of claim 21 , comprising about 45 mg of dextromethorphan.

24 . The oral sustained release delivery system of claim 21 , comprising about 60 mg of dextromethorphan.

25 . A method of decreasing the number of doses of dextromethorphan that can be administered while increasing efficacy, comprising orally administering an effective amount of threohydroxybupropion or a prodrug thereof in combination with administration of dextromethorphan to a human being in need of treatment with dextromethorphan.

26 . The method of claim 25 , wherein dextromethorphan is administered twice a day, and the treatment is more effective than administration of the same amount of dextromethorphan four times a day without administering threohydroxybupropion or a prodrug thereof.

27 . The method of claim 25 , wherein dextromethorphan is administered twice a day, and the treatment is more effective than administration of the same amount of dextromethorphan three times a day without administering threohydroxybupropion or a prodrug thereof.

28 . The method of claim 25 , wherein about 35 mg to about 120 mg of dextromethorphan is administered per day.