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 treating major depressive disorder in a CYP2D6 poor metabolizer comprising, selecting a human patient known to be a poor CYP2D6 metabolizer who is experiencing major depressive disorder, and administering, once daily in the morning for at least two weeks to the human patient, a dosage form containing 1 mg to 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion and 1 mg to 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the dextromethorphan AUC 0-12 of the human patient is increased 208% to 557% compared to extensive or ultra-extensive CYP2D6 metabolizers.
2. The method of claim 1 , wherein the dextromethorphan AUC 0-12 of the human patient is increased 340% compared to extensive or ultra-extensive CYP2D6 metabolizers.
3. The method of claim 1 , wherein approximately 26% of the dextromethorphan is excreted unchanged in the urine of the human patient.
4. The method of claim 1 , wherein a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is present in a solid dosage form.
5. 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.
6. 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.
7. The method of claim 1 , wherein the dextromethorphan is in an immediate-release formulation.
8. The method of claim 7 , wherein the bupropion is in an extended-release formulation.
9. The method of claim 1 , wherein the dosage form further contains a carbomer homopolymer and colloidal silicon dioxide.
10. The method of claim 1 , wherein the dosage form further contains crospovidone and glyceryl monocaprylocaprate.
11. The method of claim 1 , wherein the dosage form further contains L-cysteine hydrochloride monohydrate.
12. The method of claim 1 , wherein the dosage form further contains magnesium stearate and microcrystalline cellulose.
13. The method of claim 1 , wherein the dosage form further contains polyvinyl alcohol and sodium lauryl sulfate.
14. The method of claim 1 , wherein the dosage form further contains red iron oxide and stearic acid.
15. The method of claim 1 , wherein the dosage form further contains talc, titanium dioxide, or yellow iron oxide.
16. The method of claim 1 , wherein twice-daily administration of the dosage form to the human patient for 8 days would result in the human patient having about same AUC 0-12 of bupropion as compared to the AUC 0-12 of bupropion 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.
17. The method of claim 1 , wherein twice-daily administration of the dosage form to the human patient for 8 days would result in the human patient having about same C max of bupropion as compared to the C max of bupropion 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.
18. A method of treating major depressive disorder in a CYP2D6 poor metabolizer comprising, selecting a human patient known to be a poor CYP2D6 metabolizer who is experiencing major depressive disorder, and administering, once daily in the morning for at least four weeks to the human patient, a dosage form containing 1 mg to 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion and 1 mg to 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the dextromethorphan AUC 0-12 of the human patient is increased 208% to 557% compared to extensive or ultra-extensive CYP2D6 metabolizers.
19. The method of claim 18 , wherein the dextromethorphan AUC 0-12 of the human patient is increased 340% compared to extensive or ultra-extensive CYP2D6 metabolizers.
20. The method of claim 18 , wherein approximately 26% of the dextromethorphan is excreted unchanged in the urine of the human patient.
21. The method of claim 18 , wherein the dextromethorphan is in an immediate-release formulation.
22. The method of claim 21 , wherein the bupropion is in an extended-release formulation.
23. The method of claim 18 , wherein the dosage form further contains a carbomer homopolymer and colloidal silicon dioxide.
24. The method of claim 18 , wherein the dosage form further contains crospovidone and glyceryl monocaprylocaprate.
25. The method of claim 18 , wherein the dosage form further contains L-cysteine hydrochloride monohydrate.
26. The method of claim 18 , wherein the dosage form further contains magnesium stearate and microcrystalline cellulose.
27. The method of claim 18 , wherein the dosage form further contains polyvinyl alcohol and sodium lauryl sulfate.
28. The method of claim 18 , wherein the dosage form further contains red iron oxide and stearic acid.