Human Cytochrome P450 4F Enzymes and Drug Interactions

NCT ID: NCT01250535

Last Updated: 2013-01-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 19 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-12-31
• Study Completion Date: 2011-12-31

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.

Conditions

Healthy Volunteers; Drug Drug Interactions

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Warfarin plus lovastatin

Warfarin plus lovastatin

Group Type: EXPERIMENTAL

Warfarin

Intervention Type: DRUG

10 mg, po, single dose on day 7

Lovastatin

Intervention Type: DRUG

40 mg, po, once a day, days 1 through 14

Warfarin plus placebo

Warfarin plus placebo

Group Type: PLACEBO_COMPARATOR

Warfarin

Intervention Type: DRUG

10 mg, po, single dose on day 7

Placebo

Intervention Type: DRUG

po, once a day, days 1 through 14

Interventions

Warfarin

10 mg, po, single dose on day 7

Intervention Type: DRUG

Placebo

po, once a day, days 1 through 14

Intervention Type: DRUG

Lovastatin

40 mg, po, once a day, days 1 through 14

Intervention Type: DRUG

Other Intervention Names

Coumadin; Mevacor

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Kim Brouwer, PharmD, PhD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael Z Wang, PhD

Role: STUDY_DIRECTOR

University of Kansas

Kim LR Brouwer, PharmD PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Locations

University of North Carolina, Clinical and Translational Research Center (CTRC)

Chapel Hill, North Carolina, United States

Countries

United States

Other Identifiers

1R01GM089994-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

10-0576

Identifier Type: -

Identifier Source: org_study_id