Human Cytochrome P450 4F Enzymes and Drug Interactions

NCT01250535 | Completed Phase 1

• 2 other identifiers: 10-05761R01GM089994-01A1
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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

Keywords

Drug drug interactions; Warfarin; Anticoagulants; Lovastatin; Statins; CYP4F2; Vitamin K

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Pharmacokinetics

  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

  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.

Study Arms (2)

Warfarin plus lovastatin

EXPERIMENTAL

Warfarin plus lovastatin

Drug: Warfarin; Drug: Lovastatin

Warfarin plus placebo

PLACEBO COMPARATOR

Warfarin plus placebo

Drug: Warfarin; Drug: Placebo

Interventions

Warfarin DRUG

10 mg, po, single dose on day 7

Also known as: Coumadin

Warfarin plus lovastatin; Warfarin plus placebo

Placebo DRUG

po, once a day, days 1 through 14

Warfarin plus placebo

Lovastatin DRUG

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

Also known as: Mevacor

Warfarin plus lovastatin

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

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

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Interventions

Warfarin; Lovastatin

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Michael Z Wang, PhD

  University of Kansas

  STUDY DIRECTOR

• Kim LR Brouwer, PharmD PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 29, 2010
• First Posted: November 30, 2010
• Study Start: December 1, 2010
• Primary Completion: December 1, 2011
• Study Completion: December 1, 2011
• Last Updated: January 21, 2013

Record last verified: 2013-01

Locations

US (1)