Clinical trial NCT01250535: Human Cytochrome P450 4F Enzymes and Drug Interactions
Official title: Human Cytochrome P450 4F Enzymes and Drug Interactions
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Drug Drug Interactions
Keywords: Drug drug interactions
Warfarin
Anticoagulants
Lovastatin
Statins
CYP4F2
Vitamin K
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
First posted: 2010-11-30
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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

Primary outcomes:
measure: Pharmacodynamics
timeFrame: 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:
measure: Pharmacokinetics
timeFrame: 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.
measure: Pharmacokinetics
timeFrame: 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.
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina, Clinical and Translational Research Center (CTRC)
state: North Carolina
Study officials:
affiliation: University of Kansas
name: Michael Z Wang, PhD
role: STUDY_DIRECTOR
affiliation: University of North Carolina, Chapel Hill
name: Kim LR Brouwer, PharmD PhD
role: PRINCIPAL_INVESTIGATOR
References: