Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
Disclosed herein is a method of safely treating a nervous system condition with a combination of dextromethorphan and bupropion. This method is intended for patients having a neurological condition or a psychiatric condition, such as major depressive disorder, and a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype.
1. A method of improving one or more behavior associated with agitation in Alzheimer's disease in a CYP2D6 poor metabolizer comprising, selecting a human patient known to be a poor CYP2D6 metabolizer who is experiencing agitation in Alzheimer's disease, and administering, once daily in the morning for at least two weeks to the human patient, a dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein the dextromethorphan AUC 0-12 of the human patient is 208% to 557% that of the dextromethorphan AUC 0-12 of extensive or ultra-extensive CYP2D6 metabolizers, wherein the one or more behaviors associated with agitation in Alzheimer's disease comprise incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, kicking, or a combination thereof.
2. The method of claim 1 , wherein the dextromethorphan AUC 0-12 of the human patient is 340% that of the dextromethorphan AUC 0-12 of extensive or ultra-extensive CYP2D6 metabolizers.
3. The method of claim 1 , wherein once-daily administration for 8 days avoids the human patient having an about 3.4-fold increase in the AUC 0-12 of dextromethorphan as compared to the AUC 0-12 of dextromethorphan that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra-extensive CYP2D6 metabolizer.
4. The method of claim 1 , wherein once-daily administration for 8 days avoids the human patient having an about 3-fold increase in the C max of dextromethorphan as compared to the C max of dextromethorphan that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra- extensive CYP2D6 metabolizer.
5. The method of claim 1 , wherein the dextromethorphan is in an immediate-release formulation.
6. The method of claim 5 , wherein the bupropion is in an extended-release formulation.
7. The method of claim 1 , wherein the dosage form further contains a carbomer homopolymer and colloidal silicon dioxide.
8. The method of claim 1 , wherein the dosage form further contains crospovidone and glyceryl monocaprylocaprate.
9. The method of claim 1 , wherein the dosage form further contains L-cysteine hydrochloride monohydrate.
10. The method of claim 1 , wherein the dosage form further contains magnesium stearate and microcrystalline cellulose.
11. The method of claim 1 , wherein the dosage form further contains polyvinyl alcohol and sodium lauryl sulfate.
12. The method of claim 1 , wherein the dosage form further contains red iron oxide and stearic acid.
13. The method of claim 1 , wherein the dosage form further contains talc, titanium dioxide, or yellow iron oxide.
14. A method of improving one or more behavior associated with agitation in Alzheimer's disease in a CYP2D6 poor metabolizer comprising, selecting a human patient known to be a poor CYP2D6 metabolizer who is experiencing agitation in Alzheimer's disease, and administering, once daily in the morning for at least four weeks to the human patient, a dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein the dextromethorphan AUC 0-12 of the human patient is 208% to 557% that of the dextromethorphan AUC 0-12 of extensive or ultra-extensive CYP2D6 metabolizers, wherein the one or more behaviors associated with agitation in Alzheimer's disease comprise incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, kicking, or a combination thereof.
15. The method of claim 14 , wherein the dextromethorphan AUC 0-12 of the human patient is 340 % that of the dextromethorphan AUC 0-12 of extensive or ultra- extensive CYP2D6 metabolizers.
16. The method of claim 14 , wherein the dextromethorphan is in an immediate-release formulation.
17. The method of claim 16 , wherein the bupropion is in an extended- release formulation.
18. The method of claim 14 , wherein the dosage form further contains a carbomer homopolymer and colloidal silicon dioxide.
19. The method of claim 14 , wherein the dosage form further contains crospovidone and glyceryl monocaprylocaprate.
20. The method of claim 14 , wherein the dosage form further contains L-cysteine hydrochloride monohydrate.
21. The method of claim 14 , wherein the dosage form further contains magnesium stearate and microcrystalline cellulose.
22. The method of claim 14 , wherein the dosage form further contains polyvinyl alcohol and sodium lauryl sulfate.
23. The method of claim 14 , wherein the dosage form further contains red iron oxide and stearic acid.