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Human Cytochrome P450 4F Enzymes and Drug Interactions

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: NCT01250535
Recruitment Status : Completed
First Posted : November 30, 2010
Last Update Posted : January 21, 2013
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Kim Brouwer, PharmD, PhD, University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date  ICMJE November 29, 2010
First Posted Date  ICMJE November 30, 2010
Last Update Posted Date January 21, 2013
Study Start Date  ICMJE December 2010
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 29, 2010)
Pharmacodynamics [ Time Frame: Measurement will be performed before (baseline) and 2, 4, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, and 168h after co-administration of warfarin and lovastatin/placebo and during screening. ]
Measurement of Prothrombin time (PT) to assess the International Normalized Ratio (INR).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2010)
  • Pharmacokinetics [ Time Frame: Sampling will be performed before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72, 96, 120, 144, and 168 h after co-administration of warfarin and lovastatin/placebo. ]
    Vitamin K1 and vitamin K1 metabolite measured by maximum plasma concentration and AUC.
  • Pharmacokinetics [ Time Frame: Sampling will be performed before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72, 96, 120, 144, and 168 h after co-administration of warfarin and lovastatin/placebo. ]
    Pharmacokinetics for (R)- and (S)- Warfarin, and lovastatin measured by maximum plasma concentration and AUC.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Human Cytochrome P450 4F Enzymes and Drug Interactions
Official Title  ICMJE Human Cytochrome P450 4F Enzymes and Drug Interactions
Brief Summary Drug-drug interactions play an important role in clinical adverse events due to the prevalence of multi-drug therapy. Co-administration of warfarin and a statin has expanded substantially in the US over the last decades. The purpose of this study is to develop a mechanistic understanding of the role of a drug-metabolizing enzyme, CYP4F2, in the interaction between warfarin and statins. This study will test the hypothesis that lovastatin potentiates the anticoagulant effect of warfarin by inducing vitamin K-metabolizing enzyme CYP4F2 in humans, thus increasing warfarin's anticoagulant effect.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE
  • Healthy Volunteers
  • Drug Drug Interactions
Intervention  ICMJE
  • Drug: Warfarin
    10 mg, po, single dose on day 7
    Other Name: Coumadin
  • Drug: Placebo
    po, once a day, days 1 through 14
  • Drug: Lovastatin
    40 mg, po, once a day, days 1 through 14
    Other Name: Mevacor
Study Arms  ICMJE
  • Experimental: Warfarin plus lovastatin
    Warfarin plus lovastatin
    Interventions:
    • Drug: Warfarin
    • Drug: Lovastatin
  • Placebo Comparator: Warfarin plus placebo
    Warfarin plus placebo
    Interventions:
    • Drug: Warfarin
    • Drug: Placebo
Publications * Not Provided

*   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: January 17, 2013)
19
Original Estimated Enrollment  ICMJE
 (submitted: November 29, 2010)
20
Actual Study Completion Date  ICMJE December 2011
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Normal baseline clinical laboratory results including coagulation panel (prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT)), liver function tests (ALT, AST, alkaline phosphatase and total bilirubin), kidney function tests (serum creatinine and BUN), lipid panel (cholesterol, LDL-C, HDL-C, and triglycerides), and blood creatine kinase
  • Minimum weight of 110 lbs and minimum hemoglobin level at 12.5 g/dL
  • Ability to understand the informed consent form
  • Willing to abstain from grapefruit products, alcohol, and physical contact sports

Exclusion Criteria:

  • History of intolerance, allergy, or hypersensitivity to study drugs warfarin and lovastatin or any substances contained in the medication
  • History of clotting disorders, stroke, hypertension, anemia, renal insufficiency, hepatic dysfunction, platelet dysfunction, gastrointestinal bleeding, or any recent bleeding episode or trauma within 6 months
  • History of significant medical conditions that the study physician believes would increase risk (e.g., additional bleeding disorders)
  • Genotype non-homozygous for CYP2C9*1 or genotype VKORC1-1639AA
  • History of significant alcohol abuse and/or illicit drug use
  • Tobacco use within the month preceding the study
  • Woman who is pregnant or breastfeeding
  • Women who are unable to maintain adequate birth control during the study
  • Post-menopausal women on estrogen replacement
  • Chronic statin or warfarin use
  • Taking concomitant medications, both prescription and non-prescription (including herbal products, over-the-counter medications, and multivitamins), known to alter lovastatin, warfarin, or vitamin K blood levels (women stabilized on hormonal methods of birth control will be allowed to participate, and subjects stabilized on antidepressant medications will be allowed to participate)
  • Recent use of antibacterial antibiotics
  • Recent blood donation or participation in other clinical studies within past 8 weeks
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 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 NCT01250535
Other Study ID Numbers  ICMJE 10-0576
1R01GM089994-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Kim Brouwer, PharmD, PhD, University of North Carolina, Chapel Hill
Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Collaborators  ICMJE National Institutes of Health (NIH)
Investigators  ICMJE
Study Director: Michael Z Wang, PhD University of Kansas
Principal Investigator: Kim LR Brouwer, PharmD PhD University of North Carolina, Chapel Hill
PRS Account University of North Carolina, Chapel Hill
Verification Date January 2013

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