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Drug-Drug Interaction Study Between Colchicine and Diltiazem ER

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00983372
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 August 2008
Actual Primary Completion Date August 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 12, 2009)
  • Maximum Plasma Concentration (Cmax) [ Time Frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration ]
    The maximum or peak concentration that colchicine reaches in the plasma.
  • Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [ Time Frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration ]
    The area under the plasma concentration versus time curve, from time 0 to the time of the last measurable colchicine concentration (t), as calculated by the linear trapezoidal rule.
  • Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [ Time Frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration ]
    The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) was calculated as the sum of AUC(0-t) plus the ratio of the last measurable colchicine plasma concentration to the elimination rate constant.
Original Primary Outcome Measures  ICMJE
 (submitted: August 13, 2009)
  • Maximum Plasma Concentration (Cmax) [ Time Frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration ]
    The maximum or peak concentration that the drug reaches in the plasma.
  • Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [ Time Frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration ]
    The area under the plasma concentration versus time curve, from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule.
  • Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [ Time Frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration ]
    The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) was calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant.
Change History
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 Between Colchicine and Diltiazem ER
Official Title  ICMJE A One-Directional, Open-Label Drug Interaction Study to Investigate the Effects of Multiple-Dose Diltiazem ER on Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers
Brief Summary Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Extended-release diltiazem (diltiazem ER) is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of multiple doses of diltiazem ER on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. A secondary objective is to evaluate the safety and tolerability of this regimen in healthy volunteers. All study subjects will be monitored for adverse events throughout the study period.
Detailed Description Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Extended-release diltiazem (diltiazem ER) is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of multiple doses of diltiazem ER on the pharmacokinetic profile of a single 0.6mg dose of colchicine. On Day 1 after a fast of at least 10 hours, twenty-four healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given a single oral dose of colchicine (1 x 0.6 mg tablet). Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for twenty-four hours post-dose on a confined basis at times sufficient to adequately define the pharmacokinetics of colchicine. Blood sampling will then continue on a non-confined basis at 36, 48, 72, and 96 hours post-dose. After a 14-day washout period, beginning on Day 15 and continuing through Day 20 all subjects will return to the clinic for non-confined dosing of diltiazem ER (1 x 240 mg capsule daily). Administered diltiazem ER doses on these days will not necessarily be in a fasted state. On Day 21 after a fast of at least 10 hours, all study participants will receive a co-administered single oral dose of colchicine (1 x 0.6 mg tablet) and diltiazem ER (1 x 240 mg capsule). Blood samples will be drawn from all participants before dosing and for twenty-four hours post-dose on a confined basis at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of diltiazem ER at steady state. Blood sampling will then continue on a non-confined basis at 36, 48, 72, and 96 hours post-dose administration. Fasting will continue for 4 hours following the co-administered dose of colchicine and diltiazem ER. A further goal of this study is to evaluate the safety and tolerability of this regimen in healthy volunteers. Subjects will be monitored throughout participation in the study for adverse reactions to the study drug and/or procedures. Vital signs (blood pressure and pulse) will be measured pre-dose and at 1, 2, and 3 hours post-dosing on Day 1, pre-dose and 12 hours post-dosing on Day 15 (subjects will return to the study center for the 12-hour post-dose vital sign measurements), and pre-dose and 1, 2, 3 and 12 hours post-dosing on Day 21 to coincide with peak plasma concentrations of both colchicine and diltiazem. All adverse events whether elicited by query, spontaneously reported, or observed by clinic staff will be evaluated by the Investigator and reported in the subject's case report form.
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 Healthy; Adult; Volunteer; Colchicine; Pharmacokinetics; Diltiazem; Cytochrome p450 3A4; P-glycoprotein
Intervention  ICMJE
  • Drug: Colchicine
    A single dose of 0.6 mg colchicine administered alone at 7:15 am on Day 1 after an overnight fast of at least 10 hours.
    Other Name: COLCRYS™
  • Drug: Diltiazem ER
    One 240 mg diltiazem ER capsule administered daily at 7:15 am on Days 15 to 21.
    Other Name: Cardizem® CD (Biovail Pharmaceuticals, Inc.)
  • Drug: Colchicine
    A single dose of 0.6 mg colchicine administered along with diltiazem ER at 7:15 am on Day 21 after an overnight fast of at least 10 hours.
Study Arms  ICMJE
  • Active Comparator: Colchicine alone
    -colchicine baseline pharmacokinetics
    Intervention: Drug: Colchicine
  • Experimental: Colchicine with steady-state Diltiazem
    -colchicine pharmacokinetics in presence of steady-state diltiazem
    Interventions:
    • Drug: Diltiazem ER
    • 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 August 2008
Actual Primary Completion Date August 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy adults 18-45 years of age, non-smoking and non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures) with a body mass index (BMI) greater than or equal to 18 and less than or equal to 32, inclusive.

Exclusion Criteria:

  • Recent participation (within 28 days) in other research studies
  • Recent significant blood donation or plasma donation
  • Pregnant or lactating
  • Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV)
  • Recent (2-year) history or evidence of alcoholism or drug abuse
  • History or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease
  • Subjects who have used any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-glycoprotein (P-gp) within 28 days prior to the first dose and throughout the study
  • Drug allergies to colchicine or diltiazem.
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 NCT00983372
Other Study ID Numbers  ICMJE MPC-004-08-1015
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
Principal Investigator: Anthony R Godfrey, PharmD PRACS - Cetero
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