Human Cytochrome P450 4F Enzymes and Drug Interactions

Sponsor

University of North Carolina, Chapel Hill (Other)

Overall Status

Completed

CT.gov ID

NCT01250535

Collaborator

National Institutes of Health (NIH) (NIH)

Enrollment

Location

Arms

Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers Drug Drug Interactions	Drug: Warfarin Drug: Placebo Drug: Lovastatin	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

19 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Basic Science

Official Title:

Human Cytochrome P450 4F Enzymes and Drug Interactions

Study Start Date :

Dec 1, 2010

Actual Primary Completion Date :

Dec 1, 2011

Actual Study Completion Date :

Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Warfarin plus lovastatin 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 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

Arm

Intervention/Treatment

Experimental: Warfarin plus lovastatin

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

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

Outcome Measures

Primary Outcome Measures

Pharmacodynamics [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 Outcome Measures

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.]
Vitamin K1 and vitamin K1 metabolite measured by maximum plasma concentration and AUC.
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 for (R)- and (S)- Warfarin, and lovastatin measured by maximum plasma concentration and AUC.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina, Clinical and Translational Research Center (CTRC)	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

University of North Carolina, Chapel Hill
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