Healthy
Conditions
Keywords
warfarin, pharmacokinetics, drug transporter, healthy volunteer, drug interaction, rifampin
Brief summary
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.
Interventions
DRUGwarfarin plus rifampin
warfarin 7.5mg po x 1; rifampin 600mg IV x 1
DRUGwarfarin
warfarin 7.5mg po x 1
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| S- and R- Enantiomers of Warfarin (S-warfarin and R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) From 0 to 12 Hours. | 0-12 hours after warfarin dosing | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity of S-warfarin and R-warfarin | 0-120 hours after warfarin dosing | Analysis of all concentration-time data. Blood collection 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after warfarin dosing. |
| Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin | 0-120 hours after warfarin dosing | Blood collection 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after warfarin dosing. |
Countries
United States
Participant flow
Recruitment details
Healthy non-smoking volunteers from community
Pre-assignment details
All participants were medication free throughout study enrollment
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes participants randomized to receive warfarin alone then warfarin+rifampin, and those randomized to receive warfarin+rifampin then warfarin alone in the crossover design | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age Continuous | 30.1 years STANDARD_DEVIATION 9.9 |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
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.
Time frame: 0-12 hours after warfarin dosing
Population: Each of 10 participants received both treatments separated by a minimum of 14 days; treatment sequence was randomly assigned
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | S- and R- Enantiomers of Warfarin (S-warfarin and R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) From 0 to 12 Hours. | AUC (0-12 hours) of S-warfarin | 2,250 ng/ml*h | Standard Deviation 340 |
| Warfarin | S- and R- Enantiomers of Warfarin (S-warfarin and R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) From 0 to 12 Hours. | AUC (0-12 hours) of R-warfarin | 2,850 ng/ml*h | Standard Deviation 460 |
| Warfarin Plus Rifampin | S- and R- Enantiomers of Warfarin (S-warfarin and R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) From 0 to 12 Hours. | AUC (0-12 hours) of S-warfarin | 2,230 ng/ml*h | Standard Deviation 460 |
| Warfarin Plus Rifampin | S- and R- Enantiomers of Warfarin (S-warfarin and R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) From 0 to 12 Hours. | AUC (0-12 hours) of R-warfarin | 2,930 ng/ml*h | Standard Deviation 510 |
Secondary
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.
Time frame: 0-120 hours after warfarin dosing
Population: Each of 10 participants received both treatments, in randomly assigned order, separated by a minimum of 14 days
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Warfarin | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity of S-warfarin and R-warfarin | AUC(0-infinity) of S-warfarin | 8,420 ng/ml*h |
| Warfarin | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity of S-warfarin and R-warfarin | AUC(0-infinity) of R-warfarin | 18,600 ng/ml*h |
| Warfarin Plus Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity of S-warfarin and R-warfarin | AUC(0-infinity) of S-warfarin | 7,410 ng/ml*h |
| Warfarin Plus Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity of S-warfarin and R-warfarin | AUC(0-infinity) of R-warfarin | 14,100 ng/ml*h |
Secondary
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.
Time frame: 0-120 hours after warfarin dosing
Population: Each of 10 participants received both treatments, in randomly assigned order, separated by a minimum of 14 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin | Cmax of S-warfarin | 329 ng/ml | Standard Deviation 70 |
| Warfarin | Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin | Cmax of R-warfarin | 375 ng/ml | Standard Deviation 116 |
| Warfarin Plus Rifampin | Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin | Cmax of R-warfarin | 351 ng/ml | Standard Deviation 85 |
| Warfarin Plus Rifampin | Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin | Cmax of S-warfarin | 303 ng/ml | Standard Deviation 82 |