Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
This disclosure relates to methods of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan. Dosage forms, drug delivery systems, and methods related to dextromethorphan and hydroxybupropion or a prodrug of bupropion are also disclosed.
1. A method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, comprising:
administering, once or twice a day to the human being, a combination of active agents comprising:
1) bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion; and
2) dextromethorphan;
wherein the combination of active agents is administered for at least 8 consecutive days;
wherein about 40 mg to about 600 mg of dextromethorphan is administered per day;
wherein administering the combination of active agents results in an AUC 0-12 of dextromethorphan, on the eighth day, that is at least about 400 ng·hr/mL; and
wherein administering the combination of active agents results in a C max of dextromethorphan, on the eighth day, that is at least 15 times the C max of dextromethorphan that would result from administering the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion for eight consecutive days.
2. The method of claim 1 , wherein the AUC 0-12 of dextromethorphan on the eighth day is at least about 500 ng·hr/mL.
3. The method of claim 1 , wherein the C max of dextromethorphan on the eighth day is at least about 45 ng/mL.
4. The method of claim 1 wherein, on the eighth day, the plasma concentration of dextromethorphan 12 hours after administering the combination of active agents is at least about 35 ng/mL.
5. The method of claim 1 , wherein about 200 mg to about 250 mg of bupropion is administered per day.
6. The method of claim 1 , wherein about 60 mg to about 100 mg of dextromethorphan is administered per day.
7. The method of claim 1 , wherein dextromethorphan is in a form that comprises a deuterium-modified dextromethorphan.
8. The method of claim 1 , wherein the combination of active agents is administered for at least 30 days.
9. The method of claim 1 , wherein the combination of active agents is administered in a single dosage form.
10. The method of claim 1 , wherein bupropion is in a hydrochloride salt form.
11. The method of claim 1 , wherein dextromethorphan is in a salt form.
12. A method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, comprising:
administering, once or twice a day to the human being, a combination of active agents comprising:
1) bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion; and
2) dextromethorphan;
wherein the combination of active agents is administered for at least 8 consecutive days;
wherein about 40 mg to about 600 mg of dextromethorphan is administered per day;
wherein administering the combination of active agents results in a C max of dextromethorphan, on the eighth day, that is at least about 40 ng/mL; and
wherein administering the combination of active agents results in an AUC 0-12 of dextromethorphan, on the eighth day, that is at least 15 times the AUC 0-12 of dextromethorphan that would result from administering the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion for eight consecutive days.
13. The method of claim 12 , wherein the AUC 0-12 of dextromethorphan on the eighth day is at least about 450 ng·hr/mL.
14. The method of claim 12 , wherein the C max of dextromethorphan on the eighth day is at least about 50 ng/mL.
15. The method of claim 12 , wherein on the eighth day, the plasma concentration of dextromethorphan, 12 hours after the combination of active agents is administered, is at least about 30 ng/mL.
16. The method of claim 12 , wherein about 100 mg to about 110 mg of bupropion is orally administered twice a day.
17. The method of claim 12 , wherein about 105 mg of bupropion is orally administered twice a day.
18. The method of claim 12 , wherein the combination of active agents is administered for at least 60 days.
19. The method of claim 12 , wherein bupropion is in a hydrochloride salt form.