Drug Therapy, Combination
Conditions
Brief summary
This is an open-label, randomized, 2-period crossover study, to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of warfarin in combination with Tamiflu (oseltamivir) in participants stabilized on warfarin. Participants will be randomized to receive either their warfarin followed oseltamivir and warfarin, or by oseltamivir and warfarin followed by warfarin. The treatment periods will be separated by a washout period of at least 4 days. Participants will continue receiving warfarin once daily at a prescribed usual dose throughout the study.
Interventions
DRUGOseltamivir
Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.
DRUGWarfarin
Warfarin once daily, at a dose determined through titration by participants' usual hematologist.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants must have been receiving warfarin once daily for at least 4 weeks prior to Screening * Participants must have regular International Normalized ratio (INR) monitoring during warfarin therapy prior to study entry, and be willing to be trained in the use of CoaguCheck devices * INR must fall within a target range of 2.0-3.5 * Body mass index (BMI) between 18-32 kg/m\^2 inclusive
Exclusion criteria
* An INR value between screening and Day -1 lower than 2.0 or greater than 3.5 * A change in prescribed daily warfarin dose between Screening and Day -1 * History of any coagulopathy * Consumption of health products or supplements containing vitamin K * Pregnant or lactating women * Confirmed positive urine and/or blood test for drugs of abuse at Screening or Day -1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for International Normalized Ratio (INR) | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. The net AUEC(0-96 h) was calculated using the linear trapezoidal rule; this was the area under the effect-time curve and above the baseline minus the area above the curve and below the baseline during the 5-day period. An increase in INR signifies enhancement of warfarin's anticoagulant effect. |
| Change From Baseline in Maximum Observed Effect (Emax) of International Normalized Ratio (INR) | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. An increase in INR signifies enhancement of warfarin's anticoagulant effect. |
| Time to Reach Maximum Change From Baseline in International Normalized Ratio (INR) (Tmax) | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. An increase in INR signifies enhancement of warfarin's anticoagulant effect. |
| Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for Factor VII Activity | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | Factor VIIa is a protein that causes blood to clot, and low levels in the blood can cause excessive or prolonged bleeding after an injury or surgery. The net AUEC(0-96 h) was calculated using the linear trapezoidal rule; this was the area under the effect-time curve and above the baseline minus the area above the curve and below the baseline during the 5-day period. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect. kIU/L = 1000 \* international units per liter. |
| Change From Baseline in Maximum Observed Effect (Emax) in Factor VII Activity | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | Factor VIIa is a protein that causes blood to clot. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect. kIU/L = 1000 \* international units per liter. |
| Time to Reach Maximum Change From Baseline in Factor VII Activity (Tmax) | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | Factor VIIa is a protein that causes blood to clot. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect. |
| Change From Baseline in Plasma Concentration of Vitamin K1 | Pre-dose on Day 1 and 24 hours post-dose on Day 5 | Vitamin K1 is required by proteins involved in blood clotting. Food interaction with warfarin can lead to decreases in Vitamin K1 in plasma. An increase in vitamin K1 signifies enhancement of warfarin's anticoagulant effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the Cmax values (nanograms per milliliter) by the individual average dose (milligrams). |
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for Oseltamivir and Oseltamivir Carboxylate | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post-dose on Day 5 | — |
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the AUC values (hours multiplied by nanograms, per milliliter) by the individual average dose (milligrams). |
| Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5 | Oseltamivir carboxylate is an active metabolite of oseltamivir. |
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the AUC values (hours multiplied by nanograms, per milliliter) by the individual average dose (milligrams). |
| Percentage of Participants With Adverse Events | Up to Day 26 | An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5 | — |
| Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | — |
| Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5 | Oseltamivir carboxylate is an active metabolite of oseltamivir. |
| Terminal Half-life (t½) for R- and S- Warfarin | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | — |
| Oral Plasma Clearance (CL/F) for Oseltamivir | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5 | — |
| Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | — |
| Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5 | — |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants were randomized to 1 of 2 treatment sequences: warfarin then oseltamivir 75 mg and warfarin; or oseltamivir 75 mg and warfarin then warfarin. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 8.82 |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 20 | 5 / 20 |
| serious Total, serious adverse events | 1 / 20 | 0 / 20 |
Outcome results
Primary
Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for Factor VII Activity
Factor VIIa is a protein that causes blood to clot, and low levels in the blood can cause excessive or prolonged bleeding after an injury or surgery. The net AUEC(0-96 h) was calculated using the linear trapezoidal rule; this was the area under the effect-time curve and above the baseline minus the area above the curve and below the baseline during the 5-day period. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect. kIU/L = 1000 \* international units per liter.
Time frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Population: All enrolled participants with available data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Warfarin | Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for Factor VII Activity | 0.568 hours*kIU/L |
| Warfarin and Oseltamivir | Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for Factor VII Activity | 1.45 hours*kIU/L |
Primary
Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for International Normalized Ratio (INR)
INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. The net AUEC(0-96 h) was calculated using the linear trapezoidal rule; this was the area under the effect-time curve and above the baseline minus the area above the curve and below the baseline during the 5-day period. An increase in INR signifies enhancement of warfarin's anticoagulant effect.
Time frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Population: All enrolled participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Warfarin | Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for International Normalized Ratio (INR) | -2.16 hours*ratio |
| Warfarin and Oseltamivir | Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for International Normalized Ratio (INR) | -9.06 hours*ratio |
Primary
Change From Baseline in Maximum Observed Effect (Emax) in Factor VII Activity
Factor VIIa is a protein that causes blood to clot. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect. kIU/L = 1000 \* international units per liter.
Time frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Population: All enrolled participants with available data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Warfarin | Change From Baseline in Maximum Observed Effect (Emax) in Factor VII Activity | -0.0505 kIU/L |
| Warfarin and Oseltamivir | Change From Baseline in Maximum Observed Effect (Emax) in Factor VII Activity | -0.0432 kIU/L |
Primary
Change From Baseline in Maximum Observed Effect (Emax) of International Normalized Ratio (INR)
INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. An increase in INR signifies enhancement of warfarin's anticoagulant effect.
Time frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Population: All enrolled participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Warfarin | Change From Baseline in Maximum Observed Effect (Emax) of International Normalized Ratio (INR) | 0.3 ratio |
| Warfarin and Oseltamivir | Change From Baseline in Maximum Observed Effect (Emax) of International Normalized Ratio (INR) | 0.1 ratio |
Primary
Change From Baseline in Plasma Concentration of Vitamin K1
Vitamin K1 is required by proteins involved in blood clotting. Food interaction with warfarin can lead to decreases in Vitamin K1 in plasma. An increase in vitamin K1 signifies enhancement of warfarin's anticoagulant effect.
Time frame: Pre-dose on Day 1 and 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Warfarin | Change From Baseline in Plasma Concentration of Vitamin K1 | 305 nanogram per liter (ng/L) |
| Warfarin and Oseltamivir | Change From Baseline in Plasma Concentration of Vitamin K1 | 271 nanogram per liter (ng/L) |
Primary
Time to Reach Maximum Change From Baseline in Factor VII Activity (Tmax)
Factor VIIa is a protein that causes blood to clot. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect.
Time frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Population: All enrolled participants with available data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Warfarin | Time to Reach Maximum Change From Baseline in Factor VII Activity (Tmax) | 96.00 hours |
| Warfarin and Oseltamivir | Time to Reach Maximum Change From Baseline in Factor VII Activity (Tmax) | 72.00 hours |
Primary
Time to Reach Maximum Change From Baseline in International Normalized Ratio (INR) (Tmax)
INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. An increase in INR signifies enhancement of warfarin's anticoagulant effect.
Time frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Population: All enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Warfarin | Time to Reach Maximum Change From Baseline in International Normalized Ratio (INR) (Tmax) | 24.00 hours |
| Warfarin and Oseltamivir | Time to Reach Maximum Change From Baseline in International Normalized Ratio (INR) (Tmax) | 0.00 hours |
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Single Dose: Day 1) | 141 h*ng/mL | Standard Deviation 38.3 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Single Dose: Day 1) | 2990 h*ng/mL | Standard Deviation 793 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Steady State: Day 5) | 169 h*ng/mL | Standard Deviation 36.3 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Steady State: Day 5) | 5110 h*ng/mL | Standard Deviation 1630 |
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin
R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the AUC values (hours multiplied by nanograms, per milliliter) by the individual average dose (milligrams).
Time frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Total (S)-warfarin | 3610 h*ng/mL/mg | Standard Deviation 2200 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Free (S)-warfarin | 18.6 h*ng/mL/mg | Standard Deviation 13 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Total (R)-warfarin | 4140 h*ng/mL/mg | Standard Deviation 1320 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Free (R)-warfarin | 25.9 h*ng/mL/mg | Standard Deviation 7.84 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Free (R)-warfarin | 24.8 h*ng/mL/mg | Standard Deviation 6.36 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Total (S)-warfarin | 3380 h*ng/mL/mg | Standard Deviation 2100 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Total (R)-warfarin | 3870 h*ng/mL/mg | Standard Deviation 1020 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin | Free (S)-warfarin | 17.8 h*ng/mL/mg | Standard Deviation 12.3 |
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for Oseltamivir and Oseltamivir Carboxylate
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Steady state: Day 5) | 176 h*ng/mL | Standard Deviation 38.5 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Steady State: Day 5) | 7180 h*ng/mL | Standard Deviation 2550 |
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin
R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the AUC values (hours multiplied by nanograms, per milliliter) by the individual average dose (milligrams).
Time frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Total (S)-warfarin | 6770 h*ng/mL/mg | Standard Deviation 4500 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Free (S)-warfarin | 35.2 h*ng/mL/mg | Standard Deviation 26.1 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Total (R)-warfarin | 7790 h*ng/mL/mg | Standard Deviation 2480 |
| Warfarin | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Free (R)-warfarin | 49.4 h*ng/mL/mg | Standard Deviation 13.4 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Free (R)-warfarin | 48.3 h*ng/mL/mg | Standard Deviation 11.9 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Total (S)-warfarin | 6460 h*ng/mL/mg | Standard Deviation 4310 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Total (R)-warfarin | 7360 h*ng/mL/mg | Standard Deviation 1960 |
| Warfarin and Oseltamivir | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin | Free (S)-warfarin | 33.9 h*ng/mL/mg | Standard Deviation 24.1 |
Secondary
Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Single Dose: Day 1) | 88.9 nanogram per milliliter (ng/mL) | Standard Deviation 50 |
| Warfarin | Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Single Dose: Day 1) | 367 nanogram per milliliter (ng/mL) | Standard Deviation 107 |
| Warfarin | Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Steady State: Day 5) | 91.2 nanogram per milliliter (ng/mL) | Standard Deviation 47.2 |
| Warfarin | Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Steady State: Day 5) | 571 nanogram per milliliter (ng/mL) | Standard Deviation 160 |
Secondary
Maximum Plasma Concentration (Cmax) for R- and S- Warfarin
R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the Cmax values (nanograms per milliliter) by the individual average dose (milligrams).
Time frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Total (S)-warfarin | 394 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 259 |
| Warfarin | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Free (S)-warfarin | 1.87 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 1.3 |
| Warfarin | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Total (R)-warfarin | 436 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 243 |
| Warfarin | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Free (R)-warfarin | 2.70 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 1.45 |
| Warfarin and Oseltamivir | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Free (R)-warfarin | 2.37 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 0.604 |
| Warfarin and Oseltamivir | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Total (S)-warfarin | 330 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 197 |
| Warfarin and Oseltamivir | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Total (R)-warfarin | 375 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 96.3 |
| Warfarin and Oseltamivir | Maximum Plasma Concentration (Cmax) for R- and S- Warfarin | Free (S)-warfarin | 1.68 Nanogram/milliliter/milligram (ng/mL/mg) | Standard Deviation 1.13 |
Secondary
Oral Plasma Clearance (CL/F) for Oseltamivir
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Oral Plasma Clearance (CL/F) for Oseltamivir | Oseltamivir (Single Dose: Day 1) | 558 liters per hour (L/h) | Standard Deviation 134 |
| Warfarin | Oral Plasma Clearance (CL/F) for Oseltamivir | Oseltamivir (Steady State: Day 5) | 463 liters per hour (L/h) | Standard Deviation 104 |
Secondary
Oral Plasma Clearance (CL/F) for R- and S- Warfarin
Time frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Total (S)-warfarin | 0.198 liters per hour (L/h) | Standard Deviation 0.0895 |
| Warfarin | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Free (S)-warfarin | 38.5 liters per hour (L/h) | Standard Deviation 17 |
| Warfarin | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Total (R)-warfarin | 0.139 liters per hour (L/h) | Standard Deviation 0.0361 |
| Warfarin | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Free (R)-warfarin | 21.7 liters per hour (L/h) | Standard Deviation 5.74 |
| Warfarin and Oseltamivir | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Free (R)-warfarin | 22 liters per hour (L/h) | Standard Deviation 5.54 |
| Warfarin and Oseltamivir | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Total (S)-warfarin | 0.208 liters per hour (L/h) | Standard Deviation 0.0959 |
| Warfarin and Oseltamivir | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Total (R)-warfarin | 0.145 liters per hour (L/h) | Standard Deviation 0.0374 |
| Warfarin and Oseltamivir | Oral Plasma Clearance (CL/F) for R- and S- Warfarin | Free (S)-warfarin | 38.2 liters per hour (L/h) | Standard Deviation 15.1 |
Secondary
Percentage of Participants With Adverse Events
An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time frame: Up to Day 26
Population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Warfarin | Percentage of Participants With Adverse Events | 25.0 percentage of participants |
| Warfarin and Oseltamivir | Percentage of Participants With Adverse Events | 25.0 percentage of participants |
Secondary
Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate
Oseltamivir carboxylate is an active metabolite of oseltamivir.
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Single Dose: Day 1) | 1.77 hours | Standard Deviation 0.686 |
| Warfarin | Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Single Dose: Day 1) | 6.17 hours | Standard Deviation 2.07 |
| Warfarin | Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Steady State: Day 5) | 4.00 hours | Standard Deviation 3.08 |
| Warfarin | Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Steady State: Day 5) | 8.19 hours | Standard Deviation 1.9 |
Secondary
Terminal Half-life (t½) for R- and S- Warfarin
Time frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Terminal Half-life (t½) for R- and S- Warfarin | Total (S)-warfarin (n = 13, 11) | 45.4 hours | Standard Deviation 23 |
| Warfarin | Terminal Half-life (t½) for R- and S- Warfarin | Total (R)-warfarin (n = 12, 12) | 56.1 hours | Standard Deviation 26.1 |
| Warfarin and Oseltamivir | Terminal Half-life (t½) for R- and S- Warfarin | Total (S)-warfarin (n = 13, 11) | 45.6 hours | Standard Deviation 11.7 |
| Warfarin and Oseltamivir | Terminal Half-life (t½) for R- and S- Warfarin | Total (R)-warfarin (n = 12, 12) | 53.6 hours | Standard Deviation 12.2 |
Secondary
Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate
Oseltamivir carboxylate is an active metabolite of oseltamivir.
Time frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Single Dose: Day 1) | 0.50 hours |
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Single Dose: Day 1) | 4.00 hours |
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir (Steady State: Day 5) | 0.75 hours |
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir Carboxylate (Steady State: Day 5) | 4.00 hours |
Secondary
Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin
Time frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Population: All enrolled participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Total (S)-warfarin | 2.00 hours |
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Free (S)-warfarin | 14.5 hours |
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Total (R)-warfarin | 3.00 hours |
| Warfarin | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Free (R)-warfarin | 4.00 hours |
| Warfarin and Oseltamivir | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Free (R)-warfarin | 3.00 hours |
| Warfarin and Oseltamivir | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Total (S)-warfarin | 4.00 hours |
| Warfarin and Oseltamivir | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Total (R)-warfarin | 4.00 hours |
| Warfarin and Oseltamivir | Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin | Free (S)-warfarin | 3.01 hours |