Human Cytochrome P450 4F Enzymes and Drug Interactions

Study Overview
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Brief Summary
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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.

Official Title
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Human Cytochrome P450 4F Enzymes and Drug Interactions

Conditions
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Healthy Volunteers, Drug Drug Interactions

Intervention / Treatment
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* Drug: Warfarin
* Drug: Placebo
* Drug: Lovastatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug drug interactions, Warfarin, Anticoagulants, Lovastatin, Statins, CYP4F2, Vitamin K