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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers; Drug Drug Interactions
• Intervention / Treatment: Drug: Warfarin; Drug: Lovastatin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina, Clinical and Translational Research Center (CTRC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Warfarin plus lovastatin	Drug: Warfarin; 10 mg, po, single dose on day 7; Other Names: Coumadin; Drug: Lovastatin; 40 mg, po, once a day, days 1 through 14; Other Names: Mevacor
Placebo Comparator: Warfarin plus placebo	Drug: Warfarin; 10 mg, po, single dose on day 7; Other Names: Coumadin; Drug: Placebo; po, once a day, days 1 through 14

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamics	Measurement of Prothrombin time (PT) to assess the International Normalized Ratio (INR).	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics	Vitamin K1 and vitamin K1 metabolite measured by maximum plasma concentration and AUC.	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	Pharmacokinetics for (R)- and (S)- Warfarin, and lovastatin measured by maximum plasma concentration and AUC.	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.

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institutes of Health (NIH)
• Investigators: Study Director: Michael Z Wang, PhD, University of Kansas; Principal Investigator: Kim LR Brouwer, PharmD PhD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: November 29, 2010
• First Submitted That Met QC Criteria: November 29, 2010
• First Posted (Estimate): November 30, 2010

Study Record Updates

• Last Update Posted (Estimate): January 21, 2013
• Last Update Submitted That Met QC Criteria: January 17, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Warfarin; Statins; Anticoagulants; Lovastatin; Vitamin K; CYP4F2; Drug drug interactions
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticoagulants; Warfarin; Lovastatin; L 647318; Dihydromevinolin
• Other Study ID Numbers: 10-0576; 1R01GM089994-01A1 (U.S. NIH Grant/Contract)