Human Cytochrome P450 4F Enzymes and Drug Interactions

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Kim Brouwer, PharmD, PhD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01250535
First received: November 29, 2010
Last updated: January 17, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Healthy Volunteers
Drug Drug Interactions
Drug: Warfarin
Drug: Placebo
Drug: Lovastatin
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: Human Cytochrome P450 4F Enzymes and Drug Interactions

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    Measurement of Prothrombin time (PT) to assess the International Normalized Ratio (INR).


Secondary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    Pharmacokinetics for (R)- and (S)- Warfarin, and lovastatin measured by maximum plasma concentration and AUC.


Enrollment: 19
Study Start Date: December 2010
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Warfarin plus lovastatin
Warfarin plus lovastatin
Drug: Warfarin
10 mg, po, single dose on day 7
Other Name: Coumadin
Drug: Lovastatin
40 mg, po, once a day, days 1 through 14
Other Name: Mevacor
Placebo Comparator: Warfarin plus placebo
Warfarin plus placebo
Drug: Warfarin
10 mg, po, single dose on day 7
Other Name: Coumadin
Drug: Placebo
po, once a day, days 1 through 14
Other Name: Placebo

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01250535

Locations
United States, North Carolina
University of North Carolina, Clinical and Translational Research Center (CTRC)
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Investigators
Study Director: Michael Z Wang, PhD University of Kansas
Principal Investigator: Kim LR Brouwer, PharmD PhD University of North Carolina, Chapel Hill
  More Information

No publications provided

Responsible Party: Kim Brouwer, PharmD, PhD, Principal Investigator, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01250535     History of Changes
Other Study ID Numbers: 10-0576, 1R01GM089994-01A1
Study First Received: November 29, 2010
Last Updated: January 17, 2013
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by University of North Carolina, Chapel Hill:
Drug drug interactions
Warfarin
Anticoagulants
Lovastatin
Statins
CYP4F2
Vitamin K

Additional relevant MeSH terms:
Warfarin
Lovastatin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014