Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors

Authors

  • Robert A. Terkeltaub,

    Corresponding author
    1. VA San Diego Medical Center and University of California, San Diego
    • VA San Diego Medical Center, Rheumatology 111K, 3350 La Jolla Village Drive, San Diego, CA 92161
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    • Dr. Terkeltaub has received consulting fees from Altus, Ardea Biosciences, BioCryst, Novartis, Pfizer, Procter & Gamble, Regeneron, Savient, EnzymeRx, Takeda, URL Pharma, and UCB (less than $10,000 each) and grants from the Research Service of the Department of Veterans Affairs.

  • Daniel E. Furst,

    1. David Geffen School of Medicine, University of California, Los Angeles
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    • Dr. Furst has received consulting fees from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen Idec, Centocor, Gilead, Genentech/Roche, GlaxoSmithKline, Merck, Nitec, Novartis, Pfizer, and UCB (less than $10,000 each) and speaking fees (continuing medical education only) from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen Idec, Centocor, Gilead, Genentech/Roche, Merck, and Nitec (less than $10,000 each); he has received grants from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, Genentech/Roche, GlaxoSmithKline, Merck, Nitec, Novartis, Pfizer, and UCB. Salamandra, LLC (employer of Drs. DiGiacinto and Kook) is a regulatory and clinical consulting firm contracted by URL Pharma.

  • Jennifer L. DiGiacinto,

    1. Salamandra, LLC, Bethesda, Maryland
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  • Karin A. Kook,

    1. Salamandra, LLC, Bethesda, Maryland
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  • Matthew W. Davis

    1. URL Pharma, Philadelphia, Pennsylvania
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    • Dr. Davis is the Chief Medical Officer of URL Pharma and owns stock options in URL Pharma; he holds 3 patents pertaining to the dosing of colchicine with clarithromycin and ritonavir.

Errata

This article is corrected by:

  1. Errata: Erratum: Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors; Association of PPP2CA Polymorphisms With Systemic Lupus Erythematosus Susceptibility in Multiple Ethnic Groups Volume 63, Issue 11, 3521, Article first published online: 28 October 2011

  • ClinicalTrials.gov identifier: NCT00983515, NCT00983216, NCT00983931, NCT00983242, NCT00984061, NCT00983372, NCT00785486, and NCT00983294.

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.

Conclusion

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.

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