Human Cytochrome P450 4F Enzymes and Drug Interactions

Healthy Volunteers Clinical Trial

Official title:

Human Cytochrome P450 4F Enzymes and Drug Interactions

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01250535
• Other study ID #: 10-0576
• Secondary ID: 1R01GM089994-01A
• Status: Completed
• Phase: Phase 1
• First received: November 29, 2010
• Last updated: January 17, 2013
• Start date: December 2010
• Est. completion date: December 2011

Study information

• Verified date: January 2013
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: December 2011
• Est. primary completion date: December 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Drug Drug Interactions
• Healthy Volunteers

Intervention

Drug:
• Warfarin
10 mg, po, single dose on day 7
• Placebo
po, once a day, days 1 through 14
• Lovastatin
40 mg, po, once a day, days 1 through 14

Locations

Country	Name	City	State
United States	University of North Carolina, Clinical and Translational Research Center (CTRC)	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Secondary	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.	No
Secondary	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.	No