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Drug-Drug Interaction Study of Colchicine and Clarithromycin

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ClinicalTrials.gov Identifier: NCT00984061
Recruitment Status : Completed
First Posted : September 24, 2009
Results First Posted : September 24, 2009
Last Update Posted : October 15, 2009
Sponsor:
Information provided by:
Mutual Pharmaceutical Company, Inc.

Tracking Information
First Submitted Date  ICMJE August 13, 2009
First Posted Date  ICMJE September 24, 2009
Results First Submitted Date  ICMJE August 13, 2009
Results First Posted Date  ICMJE September 24, 2009
Last Update Posted Date October 15, 2009
Study Start Date  ICMJE November 2007
Actual Primary Completion Date December 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2009)
  • Maximum Plasma Concentration (Cmax) [ Time Frame: serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dose administration ]
  • Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [ Time Frame: serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dose administration ]
  • Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [ Time Frame: serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dose administration ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00984061 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Drug-Drug Interaction Study of Colchicine and Clarithromycin
Official Title  ICMJE A Pharmacokinetic Study to Evaluate the Effect of Clarithromycin on the Pharmacokinetic Profile of Colchicine in Healthy Adults
Brief Summary Clarithromycin is a potent inhibitor of the activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). CYP 3A4 plays a role in the metabolism of colchicine and P-gp is responsible for the efflux of colchicine across membranes. This study will evaluate the effect of clarithromycin-related inhibition of CYP 3A4 and P-gp on the pharmacokinetics of colchicine. It will also evaluate the safety and tolerability of concurrent administration of clarithromycin and a single dose of colchicine.
Detailed Description Clarithromycin is a potent inhibitor of the activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). CYP 3A4 plays a role in the metabolism of colchicine and P-gp is responsible for the efflux of colchicine across membranes. This open-label, one sequence, two-period, drug-drug interaction study will evaluate the effect of clarithromycin-related inhibition of CYP 3A4 and P-gp on colchicine pharmacokinetics in 24 healthy, non-smoking, non-obese (within +/- 15% of ideal body weight), male and female adult volunteers. The safety and tolerability of concurrent administration of clarithromycin and a single dose of colchicine will also be evaluated. During the first period, subjects will be confined to the study unit beginning the afternoon of the day prior to scheduled dosing (Day -1). On the morning of Day 1, after an overnight fast of at least 10 hours, subjects will be administered a single dose of colchicine 0.6 mg tablet with 240 ml of room temperature water. Blood will be drawn at times sufficient to characterize the baseline pharmacokinetics for this group. Following a 20 day washout period on Day 22, all subjects will return to the clinic to receive a supply of clarithromycin 250 mg tablets, which they will take on an outpatient basis twice daily (at 8 a.m. and 8 p.m.) without regard to meals for a total of 14 doses. Clinic staff will make telephone contact daily with subjects during this course to confirm compliance with the clarithromycin dosing regimen, and to monitor for adverse events and use of concomitant medication. On day 28 in the afternoon, subjects will again be confined to the study unit. On the morning of day 29, after an overnight fast of at least 10 hours all subjects will be administered a single dose of colchicine 0.6 mg and the final dose of clarithromycin with 240 ml water. Blood samples will be drawn at times sufficient to determine pharmacokinetic profiles of colchicine in the presence of clarithromycin at steady state. The pharmacokinetic profiles will be compared to determine the extent of drug-drug interaction.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Pharmacokinetics
Intervention  ICMJE
  • Drug: colchicine
    0.6mg tablet administered at 9am on Day 1
  • Drug: clarithromycin
    250 mg clarithromycin tablet taken on an outpatient basis twice daily at 8am and 8pm for 14 doses (starting with 8pm dose on Day 22 and concluding with 8am dose on Day 29)
  • Drug: colchicine
    0.6 mg tablet administered at 9am on Day 29
Study Arms  ICMJE
  • Experimental: colchicine alone
    colchicine baseline pharmacokinetics
    Intervention: Drug: colchicine
  • Experimental: colchicine with clarithromycin
    colchicine pharmacokinetics in presence of clarithromycin
    Interventions:
    • Drug: clarithromycin
    • Drug: colchicine
Publications * Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011 Aug;63(8):2226-37. doi: 10.1002/art.30389. Erratum in: Arthritis Rheum. 2011 Nov;63(11):3521. Dosage error in article text.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 13, 2009)
24
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE January 2008
Actual Primary Completion Date December 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy, non-smoking, adult volunteers, male and female, 18 to 45 years of age, weighing at least 55 kg and within 15% of ideal body weight, with hemoglobin >/=12 g/dL.
  • Female volunteers must be sexually abstinent for 14 days prior to the first dose and throughout the study or using acceptable birth control methods (prior to and during the study), including being postmenopausal or surgically sterile (or sexual activity restricted to a partner that is surgically sterile), hormonal contraception, an IUD, or barrier methods with spermicide. Additionally, they will be advised to remain sexually inactive or to keep the same birth control method for at least 14 days following the last dose of colchicine.

Exclusion Criteria:

  • Subjects who are pregnant or lactating
  • Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg) or hepatitis C virus (HCV)
  • Have history or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease; have used any drugs or substances known to inhibit or induce CYP enzymes and/or P-gp within 30 days prior to the first dose and throughout the study
  • Recent (2-year) history of evidence of alcoholism or drug abuse
  • Subjects who donated 50-499 ml of blood within 30 days and more than 499 ml within 56 days prior to the first dose; subjects who have donated in excess of 500 ml of blood in 14 days, 1500 ml or blood in 180 days, or 2500 ml of blood in 1 year (through completion of the study)
  • Have participated in another clinical trial within 30 days prior to dosing
  • Known and documented drug allergies to colchicine or macrolide antibiotics.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00984061
Other Study ID Numbers  ICMJE MPC-004-07-1006
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Vice President Branded Products and Medical Affairs, Mutual Pharmaceutical Company, Inc.
Study Sponsor  ICMJE Mutual Pharmaceutical Company, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Matthew Davis, MD Mutual Pharmaceutical Company, Inc.
PRS Account Mutual Pharmaceutical Company, Inc.
Verification Date October 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP