Methods of colchicine administration

• US 9,399,036 B2
• Filed: 12/10/2014
• Issued: 07/26/2016
• Est. Priority Date: 08/20/2013
• Status: Active Grant

• Current Assignee: Hikma Pharmaceuticals LLC (Hikma Pharmaceuticals PLC)
• Original Assignee: Hikma Pharmaceuticals LLC (Hikma Pharmaceuticals PLC)
• Inventors: Ducharme, Murray
• Primary Examiner(s): McCormick, Melenie
• Assistant Examiner(s): MATOS NEGRON, TAINA DEL MAR
• Application Number:
  US14/566,412
• Publication Number:
  US 20150094318A1
• Time in Patent Office: 594 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/133 having hydroxy groups, e.g. sphingosine
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings

Abstract

The invention provides improved methods for coadministration of colchicine with drugs metabolized by CYP3A4 (anciently referred to as cytochrome P450 isozyme 3A4) or the P-glycoprotein transporter, but not both. The method enables non-toxic coadministration of colchicine and the second drug at their ordinary levels safely and effectively without reducing the dose or frequency for either drug.

Claims

1. A method of administering colchicine to a patient while concomitantly administering a second drug that is an inhibitor of the cytochrome P450 3A4 isozyme (CYP3A4) but is not an inhibitor of P-glycoprotein 1 (P-gp), wherein the second drug is voriconazole, fluconazole or cimetidine wherein the method comprises:

a) administering to the patient a therapeutic fixed maintenance dose of colchicine in an amount of from about 0.6 to about 1.2 mg/day, for a maintenance period of a plurality of days;

b) after step (a), administering to the patient one or more therapeutically effective doses of the second drug; and

c) concomitantly with step (b), administering to the patient the fixed maintenance dose of colchicine of step (a) without dose reduction.

2. The method of claim 1, wherein the second drug is voriconazole administered at a dose of from 200 mg/day to 400 mg/day.

3. The method of claim 1, wherein the second drug is fluconazole administered at a dose of from 200 mg/day to 400 mg/day.

4. The method of claim 1, wherein the second drug is cimetidine administered at a dose of from 800 mg/day to 1,600 mg/day.

5. The method of claim 1, wherein said fixed maintenance dose of colchicine is 0.6 mg/day.

6. The method of claim 1, wherein said fixed maintenance dose of colchicine is 1.2 mg/day.

7. The method of claim 1, wherein said plurality of days comprises at least 7 days.

8. A method for preventing gout flares in a patient in need thereof comprising administering colchicine while concomitantly administering a second drug that is an inhibitor of the cytochrome P450 3A4 isozyme (CYP3A4) but is not an inhibitor of P-glycoprotein 1 (P-gp), wherein the second drug is voriconazole, fluconazole or cimetidine wherein the method comprises:

a) administering to the patient a therapeutic fixed maintenance dose of colchicine in an amount of from about 0.6 to about 1.2 mg/day, for a maintenance period of a plurality of days;

b) after step (a), administering to the patient one or more therapeutically effective doses of the second drug; and

c) concomitantly with step (b), administering to the patient the fixed maintenance dose of colchicine of step (a) without dose reduction.

9. A method of administering colchicine to a patient while concomitantly administering a second drug that is an inhibitor of the cytochrome P450 3A4 isozyme (CYP3A4) but is not an inhibitor of P-glycoprotein 1 (P-gp), wherein the second drug is voriconazole, fluconazole, or cimetidine, wherein the method comprises:

a) administering to the patient a plurality of therapeutically effective doses of the inhibitor of cytochrome P450 3A4 isoenzyme (CYP3A4) for a plurality of days without administering colchicine;

b) after step (a), administering to the patient one or more fixed maintenance doses of colchicine in an amount from about 0.6 to about 1.2 mg/day;

c) concomitantly with step (b) administering to the patient a plurality of effective doses of the inhibitor of cytochrome P450 3A4 isoenzyme (CYP3A4);

d) after step (c), discontinuing administration of the inhibitor of cytochrome P450 3A4 isoenzyme (CYP3A4) and continuing to administer the fixed maintenance dose of colchicine administered in step (b) without dose adjustment.

10. A method of preventing gout flares in a patient in need thereof comprising administering colchicine while concomitantly administering a second drug that is an inhibitor of the cytochrome P450 3A4 isozyme (CYP3A4) but is not an inhibitor of P-glycoprotein 1 (P-gp), wherein the second drug is voriconazole, fluconazole, or cimetidine, wherein the method comprises:

a) administering to the patient a plurality of therapeutically effective doses of the inhibitor of the cytochrome P450 3A4 isozyme (CYP3A4) for a plurality of days without administering colchicine;

b) after step (a), administering to the patient one or more fixed maintenance doses of colchicine in an amount from about 0.6 to about 1.2 mg/day;

c) concomitantly with step (b) administering to the patient a plurality of effective doses of the inhibitor of the cytochrome P450 3A4 isozyme (CYP3A4);

d) after step (c), discontinuing administration of the inhibitor of the cytochrome P450 3A4 isozyme (CYP3A4) and continuing to administer the fixed maintenance dose of colchicine administered in step (b) without dose adjustment.