In this report, researchers describe their attempt to improve the safety of colchicine dosing algorithms. They conducted seven separate drug-drug interaction (DDI) studies with single-dose colchicine to elucidate in vivo effects of concomitant colchicine and 7 known inhibitors of CYP3A4/P-gp on colchicine pharmacokinetics.

• Cyclosporine
• Ketoconazole
• Ritonavir
• Macrolide antibiotics (clarithromycin, azithromycin)
• Calcium channel blockers (verapamil, diltiazem)

All studies were open label, non-randomised, single-centre, one-sequence, two-period DDI experiments, using two 0.6-mg doses of colchicine, separated by a minimum 14-day wash-out, and followed by the approved dosing regimen of CYP3A4/P-gp inhibitor. Plasma colchicine concentrations were determined, and pharmacokinetic parameters calculated.

The following findings were reported:

• Ratios of Cmax, and AUC0-∞ for colchicine plus CYP3A4/P-gp inhibitors vs. colchicine (alone) across these studies were >125% with the exception of azithromycin.

• Significant DDIs were present when single doses of colchicine are co-administered with most of the selected CYP3A4/P-gp inhibitors.

• Recommended dose reductions of 33-66% for acute gout, and 50-75% for colchicine prophylaxis therapy, were calculated for concomitant therapy with each agent, with exception of no dose adjustment for azithromycin.

The researchers note these studies provide quantitative evidence on drug interactions and necessary dosage adjustments for colchicine if continued during therapy with multiple CYP3A4/P-gp inhibitors; namely that there is a need for specific dose reductions of colchicine with use of two calcium channel blockers (verapamil, diltiazem), whilst dose adjustment was not required when used concomitantly with azithromycin.