Claims for Patent: 9,789,108

Summary for Patent: 9,789,108

Title:	Methods of colchicine administration
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.
Inventor(s):	Murray Ducharme
Assignee:	Hikma Pharmaceuticals LLC
Application Number:	US14/566,307
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,789,108
Patent Claims:	1. A method of administering a fixed maintenance dose of colchicine in a patient concomitantly administered voriconazole without dose reduction of colchicine, comprising inducing in said patient a pharmacokinetic profile of colchicine selected from: a) a pharmacokinetic profile of colchicine comprising a mean Cmax of 2058.2±44.9% pg/mL, a median Tmax of 1.5±35.4% hours, a mean AUCT of 20730.8±36.9% pg·h/mL where T equals 72 hours, a mean AUC∞ of 24100.1±37.3% pg·h/mL, and a mean elimination half life of 31.30 hours±17.0%; and b) a pharmacokinetic profile of colchicine comprising a Cmax of 1834.9±30.8% pg/mL (geometric least squares means), an AUCT of 19502.6±28.0% pg·h/mL (geometric least squares mean) where T equals 72 hours, and an AUC∞ of 22663.5±27.2% pg·h/mL (geometric least squares mean); wherein the mean AUCT or AUCT (geometric least squares mean) of colchicine in the pharmacokinetic profile of the patient is about the same as a mean AUCT or AUCT (geometric least squares mean) of colchicine, respectively, in a pharmacokinetic profile in the patient when colchicine is administered in the same fixed maintenance dose without concomitant administration of voriconazole. 2. The method of claim 1, comprising inducing in said patient a pharmacokinetic profile of colchicine comprising a mean Cmax of 2058.2 pg/mL, a median Tmax of 1.5 hours, a mean AUCT of 20730.8 pg·h/mL where T equals 72 hours, a mean AUC∞ of 24100.1 pg·h/mL, and a mean elimination half life of 31.30 hours. 3. The method of claim 1, comprising inducing in said patient a pharmacokinetic profile of colchicine comprising a Cmax of 1834.9 pg/mL (geometric least squares mean), an AUCT of 19502.6 pg·h/mL (geometric least squares mean) where T equals 72 hours, and an AUC∞ of 22663.5 pg·h/mL (geometric least squares mean). 4. The method of claim 1 for the prevention of gout. 5. The method of claim 1, wherein the fixed maintenance dose of colchicine is 0.6 mg/day. 6. The method of claim 1, wherein the voriconazole is administered in a dose of 200 mg/day to 400 mg/day. 7. A method of administering a fixed maintenance dose of colchicine to a patient concomitantly administered voriconazole, comprising inducing in the patient following concomitant administration of colchicine and voriconazole a pharmacokinetic profile comprising an AUCT of colchicine that is about 104% to about 110% of an AUCT of colchicine in a pharmacokinetic profile of the patient following administration of the same fixed maintenance dose of colchicine without concomitant administration of voriconazole. 8. The method of claim 7, wherein the pharmacokinetic profile in the patient following concomitant administration of colchicine and voriconazole comprises a mean Cmax of colchicine that is less than the mean Cmax of colchicine in the patient following administration of colchicine without concomitant administration of voriconazole. 9. The method of claim 7, wherein the pharmacokinetic profile in the patient following concomitant administration of colchicine and voriconazole comprises a mean Cmax of colchicine of about 2100 pg/mL. 10. The method of claim 7, wherein the pharmacokinetic profile in the patient following concomitant administration of colchicine and voriconazole comprises a Tmax of colchicine of about 1.5 hours. 11. The method of claim 7, wherein the pharmacokinetic profile in the patient following concomitant administration of colchicine and voriconazole comprises an AUCT of colchicine of about 21000 pg·h/mL. 12. The method of claim 7, wherein the pharmacokinetic profile in the patient following concomitant administration of colchicine and voriconazole comprises an elimination half-life of colchicine of about 31 hours. 13. The method of claim 7, wherein the fixed maintenance dose of colchicine is 0.6 mg/day to 1.2 mg/day and wherein the voriconazole is administered at a dose of from 200 mg/day to 400 mg/day. 14. The method of claim 13, wherein the fixed maintenance dose of colchicine is 0.6 mg/day and the voriconazole is administered at a dose of 400 mg/day. 15. A method of administering a fixed maintenance dose of colchicine to a patient concomitantly administered voriconazole, comprising inducing in the patient following concomitant administration of colchicine and voriconazole a pharmacokinetic profile comprising a geometric least squares mean AUCT of colchicine that is 89% to 133% of the geometric least squares mean AUCT of colchicine in the pharmacokinetic profile of the patient following administration of the same fixed maintenance dose of colchicine without concomitant administration of voriconazole. 16. The method of claim 15, wherein the pharmacokinetic profile in the patient following concomitant administration of colchicine and voriconazole comprises a geometric least squares mean AUC∞ of colchicine that is 91% to 135% of the geometric least squares mean AUC∞ of colchicine in the pharmacokinetic profile of the patient following administration of colchicine without concomitant administration of voriconazole. 17. The method of claim 15, wherein the pharmacokinetic profile in the patient following concomitant administration of colchicine and voriconazole comprises a geometric least squares mean Cmax of colchicine that is 64% to 99% of the geometric least squares mean Cmax of colchicine in the pharmacokinetic profile of the patient following administration of colchicine without concomitant administration of voriconazole. 18. A method of administering a fixed maintenance dose of colchicine in a patient concomitantly administered a second compound selected from fluconazole and cimetidine without dose reduction of colchicine, comprising inducing in said patient a pharmacokinetic profile of colchicine selected from: (i) when the second compound is fluconazole: a) a pharmacokinetic profile of colchicine comprising a mean Cmax of 2299.2±57.6% pg/mL, a median Tmax of 1.38±25.4% hours, a mean AUCT of 21270.7±33.6% pg·h/mL where T equals 72 hours, and a mean elimination half life of 34.51±14.8% hours; and b) a pharmacokinetic profile of colchicine comprising a Cmax of 2046.3±27.1% pg/mL (geometric least squares means), an AUCT of 20364.2±22.4% pg·h/mL (geometric least squares mean) where T equals 72 hours, and an AUC∞ of 24386.8±22.5% pg·h/mL (geometric least squares mean); and (ii) when the second compound is cimetidine: a) a pharmacokinetic profile of colchicine comprising a mean Cmax of 2108.7±50.2% pg/mL, a median Tmax of 1.03±30.2% hours, a mean AUCT of 18082.1±41.6% pg·h/mL where T equals 72 hours, and a mean elimination half life of 31.54±11.1% hours; and b) a pharmacokinetic profile of colchicine comprising a Cmax of 1878.1±29.3% pg/mL (geometric least squares means), an AUCT of 16719.0±18.7% pg·h/mL (geometric least squares mean) where T equals 72 hours, and an AUC∞ of 19334.3±19.4% pg·h/mL (geometric least squares mean); wherein the mean AUCT or AUCT (geometric least squares mean) of colchicine in the pharmacokinetic profile of the patient is about the same as a mean AUCT or AUCT (geometric least squares mean) of colchicine, respectively, in a pharmacokinetic profile in the patient when colchicine is administered in the same fixed maintenance dose without concomitant administration of the second compound.