Drug Interaction Study of Rifampin and Warfarin in Healthy Volunteers.

Study Overview
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Brief Summary
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The purpose of this study is to determine the importance of uptake drug transporters in the drug disposition of warfarin. We predict that the elimination of warfarin will be decreased when co-dosed with an inhibitor of uptake drug transporters.

Official Title
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The Effects of Rifampin on the Pharmacokinetics of Warfarin in Healthy Volunteers.

Conditions
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Healthy

Intervention / Treatment
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* Drug: warfarin plus rifampin
* Drug: warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 18-60 years of age; Healthy adult with no active medical problems or significant chronic diseases as determined by the study doctor based on history, physical exam and laboratory evaluations; BMI between 18.5 - 30 kg/m2; Taking no medications 2 weeks before and during the study enrollment, including drugs of abuse, prescription or over-the-counter (OTC) medications (except acetaminophen); Subjects able to maintain adequate birth control during the study independent of hormonal contraceptive use; Be able to provide written informed consent and comply with requirements of the study; Avoid eating grapefruit and drinking grapefruit juice from 7 days before the first study day until completion of the entire study; Abstinence from alcoholic beverages, caffeinated beverages and orange juice from 6pm the night before a study day until completion of that study day; Avoidance of contact sports and/or other activities with significant risk of trauma injury for 7 days after each study day. Fast from food and beverages at least 8 hours prior to medication dosing; Be able to read, speak and understand English Exclusion Criteria: Subjects on prescription or chronic over-the counter medications (including hormonal contraceptives); Subjects with known allergy to warfarin and/or rifampin; Subjects who are not homozygous for cytochrome P450 2C9 (CYP2C9 *1) (known poor metabolizers). Subjects with a history or diagnosis of hemorrhagic tendencies or blood dyscrasias; Subjects with liver failure or liver function test (LFT) results >2x upper limit of normal; Subjects with clinically significant elevations in international normalized ratio (INR), prothrombin (PT), prothrombin time (PTT), serum creatinine (SCr), blood urea nitrogen (BUN) or other screening laboratory tests as determined by study physician; Subjects with Hct <30 mg/dL; Subjects with history of GI bleed or peptic ulcer disease; Subjects with a recent history of trauma; Subjects with a recent history of or upcoming plan of surgery; Subjects who smoke tobacco; Subjects with ongoing alcohol or illegal drug use; Subjects who are pregnant, lactating or attempting to conceive; Subjects unable to maintain adequate birth control during the study; Subjects unable to follow protocol instructions or protocol criteria.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: warfarin then warfarin plus rifampin<br> | Drug: warfarin plus rifampin<br>* warfarin 7.5mg po x 1; rifampin 600mg IV x 1<br>Drug: warfarin<br>* warfarin 7.5mg po x 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| S- and R- Enantiomers of Warfarin (S-warfarin and R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) From 0 to 12 Hours. | Uptake effects on warfarin pharmacokinetics during time period of hepatic organic anion-transporting polypeptide (OATP) inhibition by rifampin. Blood collection 1, 2, 4, 6, 8, and 12 hours after warfarin dosing. | 0-12 hours after warfarin dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity of S-warfarin and R-warfarin | Analysis of all concentration-time data. Blood collection 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after warfarin dosing. | 0-120 hours after warfarin dosing | 
| Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin | Blood collection 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after warfarin dosing. | 0-120 hours after warfarin dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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warfarin, pharmacokinetics, drug transporter, healthy volunteer, drug interaction, rifampin