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NCT Number: NCT01250535

Human Cytochrome P450 4F Enzymes and Drug Interactions

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.

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Key information

Conditions

Healthy Volunteers Drug Drug Interactions

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

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

Chapel Hill, North Carolina, 27599, United States

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Warfarin

Drug

10 mg, po, single dose on day 7

Other names: Coumadin

Placebo

Drug

po, once a day, days 1 through 14

lovastatin

Drug

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

Other names: Mevacor

Primary outcomes

  1. 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).

Secondary outcomes

  1. 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.

  2. 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.

Sponsors and collaborators

Lead sponsor

University of North Carolina, Chapel Hill

Other

Collaborators

  • National Institutes of Health (NIH)

Registry information

Important dates

Study start
2010
Primary completion
2011
Study completion
2011
First posted
Nov 30, 2010
Registry last updated
Jan 21, 2013

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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