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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Drug Therapy, Combination

Intervention / Treatment
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* Drug: Oseltamivir
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Warfarin Then Warfarin and Oseltamivir<br>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<br>* Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.<br>* Other names: Tamiflu®;Drug: Warfarin<br>* Warfarin once daily, at a dose determined through titration by participants' usual hematologist.<br>|
| Experimental: First Warfarin and Oseltamivir Then Warfarin<br>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<br>* Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.<br>* Other names: Tamiflu®;Drug: Warfarin<br>* Warfarin once daily, at a dose determined through titration by participants' usual hematologist.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | 
| 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. | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | 
| 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. | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | 
| 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. | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | 
| 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. | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | 
| 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. | Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5) | 
| 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. | Pre-dose on Day 1 and 24 hours post-dose on Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate | Oseltamivir carboxylate is an active metabolite of 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 | 
| 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 | Oseltamivir carboxylate is an active metabolite of 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 | 
| 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 | 
| 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). | Pre-dose; 1, 2, 4, 8, 12, 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 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 | 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). | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | 
| 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 | 
| 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). | Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5 | 
| 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. | Up to Day 26 |