Human Cytochrome P450 4F Enzymes and Drug Interactions

University of North Carolina (UNC)

Status and phase: Completed; Phase 1

Conditions: Healthy Volunteers; Drug Drug Interactions

Treatments: Drug: Placebo; Drug: Warfarin; Drug: Lovastatin

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01250535

10-0576

1R01GM089994-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Enrollment: 19 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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19 participants in 2 patient groups, including a placebo group

Warfarin plus lovastatin

Experimental group

Description:

Warfarin plus lovastatin

Treatment:

Drug: Lovastatin

Drug: Warfarin

Warfarin plus placebo

Placebo Comparator group

Description:

Warfarin plus placebo

Treatment:

Drug: Placebo

Drug: Warfarin