title: Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors.
abstract: OBJECTIVE
  Drug-drug interactions can limit the safety of colchicine for treating rheumatic diseases. Seven separate drug-drug interaction (DDI) studies were performed to elucidate the in vivo effects of concomitant treatment with colchicine and known inhibitors of cytochrome P450 3A4 (CYP3A4)/P-glycoprotein (cyclosporine, ketoconazole, ritonavir, clarithromycin, azithromycin, verapamil ER [extended release]), and diltiazem ER) on the pharmacokinetics of colchicine. The objective was to develop colchicine-dosing algorithms with improved safety.
  
  
  METHODS
  All studies were open-label, non-randomized, single-center, one-sequence, two-period DDI experiments, using two 0.6-mg doses of colchicine, separated by a minimum 14-day washout period, followed by administration of the approved on-label regimen of known CYP3A4/P-glycoprotein inhibitors. Plasma concentrations of colchicine, but not the reference CYP3A4/P-glycoprotein inhibitors, were determined, and the pharmacokinetic parameters were calculated.
  
  
  RESULTS
  The ratios of the maximum concentration and area under the curve from time 0 to infinity for colchicine plus CYP3A4/P-glycoprotein inhibitors versus colchicine alone were >125% across all studies, with the exception of studies involving azithromycin. Significant DDIs were present when single doses of colchicine were coadministered with most of the selected CYP3A4/P-glycoprotein inhibitors. Recommended colchicine dose reductions of 33-66% for the treatment of acute gout and 50-75% for prophylaxis were calculated for concomitant therapy with each agent, with the exception of no dose adjustment when colchicine is used in combination with azithromycin.
  
  
  CONCLUSIONS
  These studies provide quantitative evidence regarding drug interactions and necessary adjustments in the dose of colchicine if colchicine treatment is continued during therapy with multiple CYP3A4/P-glycoprotein inhibitors. We demonstrated the need for specific reductions in the dose of colchicine when it is used in combination with 2 broadly prescribed calcium channel blockers (verapamil ER and diltiazem ER) and that the dose of colchicine does not need to be adjusted when it is used in combination with azithromycin.
authors.affiliation: VA San Diego Medical Center, San Diego, CA 92161, USA. rterkeltaub@ucsd.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Terkeltaub
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Digiacinto
authors.forename: Karin A
authors.initials: KA
authors.lastname: Kook
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Davis
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D003078:Colchicine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003078:Colchicine