A Pharmacokinetics, Pharmacodynamics and Safety Study of Warfarin in Combination With Tamiflu (Oseltamivir)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02780622
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 5
• Patients Per Site Per Month: 4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Drug Therapy, Combination	Drug: Oseltamivir; Drug: Warfarin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: An Open-label, Randomized 2-period Crossover Study to Investigate the Pharmacodynamics, Pharmacokinetics, Safety and Tolerability of Warfarin in Combination With Oseltamivir in Volunteers Stabilized on Warfarin Therapy
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: First Warfarin Then Warfarin and Oseltamivir Participants will receive warfarin (on Days 1-5) in Treatment Period 1, followed by a washout period of at least 4 days (maximum 8 days). Participants will then receive oseltamivir 75 milligram (mg) (orally twice daily on Days 1-4 and once on Day 5) and warfarin in Treatment Period 2, and attend a follow-up visit 4-12 days after the last dose in Treatment Period 2. Participants will continue receiving warfarin once daily at a prescribed usual dose throughout the study.	Drug: Oseltamivir; Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.; Other Names: Tamiflu® ; Drug: Warfarin; Warfarin once daily, at a dose determined through titration by participants' usual hematologist.
Experimental: First Warfarin and Oseltamivir Then Warfarin Participants will receive oseltamivir 75 mg (orally twice daily on Days 1-4 and once on Day 5) and warfarin in Treatment Period 1, followed by a washout period of at least 4 days (maximum 8 days). Participants will then receive warfarin (on Days 1-5) in Treatment Period 2, and attend a follow-up visit 4-12 days after the last dose in Treatment Period 2. Participants will continue receiving warfarin once daily at a prescribed usual dose throughout the study.	Drug: Oseltamivir; Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.; Other Names: Tamiflu® ; Drug: Warfarin; Warfarin once daily, at a dose determined through titration by participants' usual hematologist.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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 Outcome Measures

1. 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.

2. 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]

3. 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.

4. Terminal Half-life (t½) for R- and S- Warfarin [Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5]

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]

6. Oral Plasma Clearance (CL/F) for R- and S- Warfarin [Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5]

7. 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]

8. 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).

9. 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]

10. 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).

11. 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]

12. 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).

13. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Surrey		United Kingdom	CR7 7YE

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02780622
• Other Study ID Numbers: WP21272; 2007-005037-11
• First Posted: May 23, 2016
• Last Update Posted: Oct 26, 2016
• Last Verified: Jun 1, 2016

• Additional relevant MeSH terms: Oseltamivir; Warfarin

Study Results

Participant Flow

Arm/Group Title	First Warfarin Then Warfarin and Oseltamivir	First Warfarin and Oseltamivir Then Warfarin
Arm/Group Description	Participants received warfarin (on Days 1-5) in Treatment Period 1, followed by a washout period of at least 4 days (maximum 8 days). Participants then received oseltamivir 75 milligram (mg) (orally twice daily on Days 1-4 and once on Day 5) and warfarin in Treatment Period 2, and attended a follow-up visit 4-12 days after the last dose in Treatment Period 2. Participants continued to receive warfarin once daily at a prescribed usual dose throughout the study.	Participants received oseltamivir 75 mg (orally twice daily on Days 1-4 and once on Day 5) and warfarin in Treatment Period 1, followed by a washout period of at least 4 days (maximum 8 days). Participants then received warfarin (on Days 1-5) in Treatment Period 2, and attended a follow-up visit 4-12 days after the last dose in Treatment Period 2. Participants continued to receive warfarin once daily at a prescribed usual dose throughout the study.
Period Title: Treatment Period 1
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Participants were randomized to 1 of 2 treatment sequences: warfarin then oseltamivir 75 mg and warfarin; or oseltamivir 75 mg and warfarin then warfarin.
Overall Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.4 (8.82)
Sex: Female, Male (Count of Participants)
Female	6 30%
Male	14 70%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for International Normalized Ratio (INR)
Description	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)

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Mean (Full Range) [hours*ratio]	-2.16	-9.06

2. Primary Outcome

Title	Change From Baseline in Maximum Observed Effect (Emax) of International Normalized Ratio (INR)
Description	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)

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Mean (Full Range) [ratio]	0.3	0.1

3. Primary Outcome

Title	Time to Reach Maximum Change From Baseline in International Normalized Ratio (INR) (Tmax)
Description	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)

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Median (Full Range) [hours]	24.00	0.00

4. Primary Outcome

Title	Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for Factor VII Activity
Description	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)

Outcome Measure Data

Analysis Population Description

All enrolled participants with available data.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	19	19
Mean (Full Range) [hours*kIU/L]	0.568	1.45

5. Primary Outcome

Title	Change From Baseline in Maximum Observed Effect (Emax) in Factor VII Activity
Description	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)

Outcome Measure Data

Analysis Population Description

All enrolled participants with available data.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	19	19
Mean (Full Range) [kIU/L]	-0.0505	-0.0432

6. Primary Outcome

Title	Time to Reach Maximum Change From Baseline in Factor VII Activity (Tmax)
Description	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)

Outcome Measure Data

Analysis Population Description

All enrolled participants with available data.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	19	19
Median (Full Range) [hours]	96.00	72.00

7. Primary Outcome

Title	Change From Baseline in Plasma Concentration of Vitamin K1
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Mean (Full Range) [nanogram per liter (ng/L)]	305	271

8. Secondary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin and Oseltamivir
Arm/Group Description	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20
Oseltamivir (Single Dose: Day 1)	0.50
Oseltamivir Carboxylate (Single Dose: Day 1)	4.00
Oseltamivir (Steady State: Day 5)	0.75
Oseltamivir Carboxylate (Steady State: Day 5)	4.00

9. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Total (S)-warfarin	2.00	4.00
Free (S)-warfarin	14.5	3.01
Total (R)-warfarin	3.00	4.00
Free (R)-warfarin	4.00	3.00

10. Secondary Outcome

Title	Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin and Oseltamivir
Arm/Group Description	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20
Oseltamivir (Single Dose: Day 1)	1.77 (0.686)
Oseltamivir Carboxylate (Single Dose: Day 1)	6.17 (2.07)
Oseltamivir (Steady State: Day 5)	4.00 (3.08)
Oseltamivir Carboxylate (Steady State: Day 5)	8.19 (1.90)

11. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Total (S)-warfarin (n = 13, 11)	45.4 (23.0)	45.6 (11.7)
Total (R)-warfarin (n = 12, 12)	56.1 (26.1)	53.6 (12.2)

12. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin and Oseltamivir
Arm/Group Description	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20
Oseltamivir (Single Dose: Day 1)	558 (134)
Oseltamivir (Steady State: Day 5)	463 (104)

13. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Total (S)-warfarin	0.198 (0.0895)	0.208 (0.0959)
Free (S)-warfarin	38.5 (17)	38.2 (15.1)
Total (R)-warfarin	0.139 (0.0361)	0.145 (0.0374)
Free (R)-warfarin	21.7 (5.74)	22 (5.54)

14. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin and Oseltamivir
Arm/Group Description	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20
Oseltamivir (Single Dose: Day 1)	88.9 (50.0)
Oseltamivir Carboxylate (Single Dose: Day 1)	367 (107)
Oseltamivir (Steady State: Day 5)	91.2 (47.2)
Oseltamivir Carboxylate (Steady State: Day 5)	571 (160)

15. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) for R- and S- Warfarin
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Total (S)-warfarin	394 (259)	330 (197)
Free (S)-warfarin	1.87 (1.30)	1.68 (1.13)
Total (R)-warfarin	436 (243)	375 (96.3)
Free (R)-warfarin	2.70 (1.45)	2.37 (0.604)

16. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin and Oseltamivir
Arm/Group Description	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20
Oseltamivir (Steady state: Day 5)	176 (38.5)
Oseltamivir Carboxylate (Steady State: Day 5)	7180 (2550)

17. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Total (S)-warfarin	6770 (4500)	6460 (4310)
Free (S)-warfarin	35.2 (26.1)	33.9 (24.1)
Total (R)-warfarin	7790 (2480)	7360 (1960)
Free (R)-warfarin	49.4 (13.4)	48.3 (11.9)

18. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin and Oseltamivir
Arm/Group Description	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20
Oseltamivir (Single Dose: Day 1)	141 (38.3)
Oseltamivir Carboxylate (Single Dose: Day 1)	2990 (793)
Oseltamivir (Steady State: Day 5)	169 (36.3)
Oseltamivir Carboxylate (Steady State: Day 5)	5110 (1630)

19. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Total (S)-warfarin	3610 (2200)	3380 (2100)
Free (S)-warfarin	18.6 (13.0)	17.8 (12.3)
Total (R)-warfarin	4140 (1320)	3870 (1020)
Free (R)-warfarin	25.9 (7.84)	24.8 (6.36)

20. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Warfarin	Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.	Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
Measure Participants	20	20
Number [percentage of participants]	25.0 125%	25.0 NaN

Adverse Events

Time Frame	Five days for each treatment period (Up to Day 26)
Adverse Event Reporting Description	All enrolled participants.
Arm/Group Title	Warfarin		Warfarin and Oseltamivir
Arm/Group Description	Participants who received Warfarin alone at a prescribed usual dose in treatment period 1 or treatment period 2.		Participants who received warfarin at a prescribed usual dose along with oseltamivir 75 mg, orally twice daily on Days 1-4 and once on Day 5 in treatment period 1 or treatment period 2.
All Cause Mortality
	Warfarin		Warfarin and Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Warfarin		Warfarin and Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		0/20 (0%)
Cardiac disorders
Angina pectoris	1/20 (5%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Warfarin		Warfarin and Oseltamivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/20 (20%)		5/20 (25%)
Gastrointestinal disorders
Diarrhoea	0/20 (0%)		1/20 (5%)
General disorders
Venipuncture site swelling	0/20 (0%)		1/20 (5%)
Infections and infestations
Fungal skin infection	1/20 (5%)		0/20 (0%)
Oral herpes	1/20 (5%)		0/20 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	0/20 (0%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)		0/20 (0%)
Joint effusion	1/20 (5%)		0/20 (0%)
Nervous system disorders
Headache	0/20 (0%)		2/20 (10%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	0/20 (0%)		1/20 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.