Drug interaction study to investigate the the PD, PK, safety and tolerability of warfarin in combination with oseltamivir in volunteers stabilized on warfarin therapy.
Conditions
Interventions
Trade Name: Tamiflu
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Oseltamivir phosphate
CAS Number: 204255-11-8
Current Sponsor code: Ro 64-0796
Concentration unit: mg milligram(s)
Concentra
Sponsors
F.Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female subjects, 18-85 years of age, inclusive. 2. Subjects must have been receiving warfarin once daily for at least 4 weeks prior to screening. 3. Subjects must have regular INR monitoring during warfarin therapy prior to study entry, and willing to be trained in the use of CoaguChek® devices. 4. INR must fall within a target range of 2.0-3.5 (as determined by CoaguChek® or a clinical laboratory INR test). 5. A BMI between 18-32 kg/m2 inclusive 6. Able to participate, and willing to give written informed consent and to comply with the study restrictions 7. Confirmation by dietician questionnaire of a reasonably balanced diet Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. An INR value between screening and Day -1 lower than 2.0 or greater than 3.5. 2. A change in their prescribed daily warfarin dose between screening and Day -1. 3. History of any coagulopathy for example von Willebrand’s disease. 4. Consumption of health products or supplements containing Vitamin K. 5. If capable of reproduction, unwilling to use an effective (barrier) form of contraception (post-menopausal status must be verified by negative hormone panel). 6. Positive pregnancy test at screening or Day -1 and lactating women. 7. Confirmed positive urine and/or blood test for drugs of abuse at screening or Day -1. 8. History of drug or alcohol abuse. 9. Donation or loss of blood over 500 mL within three months prior to screening. 10. Participation in an investigational drug or device study within three months prior to screening. 11. Smokers of >5 cigarettes or equivalent in tobacco per day (>3 pipefulls or >3 cigars per day). 12. Use of any prescription drug, over the counter medication or herbal product, known to be an inducer or inhibitor of CYP450 enzymes or any drugs included in the list of prohibited medications, taken within 7 days of first dose of study drug, or 5 times the elimination half-life of the medication, whichever is longer, unless the patient/volunteer is stable on the stated medication and it has been taken for a period of = 3 months. 13. Consistent supine systolic blood pressure (SBP) greater than 160 or less than 80 and diastolic blood pressure (DBP) greater than 90 or less than 60 mm Hg between screening and Day -1. 14. Consistent supine heart rate (HR) at rest greater than 90 less than 45 beats per minute (bpm) between screening and Day -1. 15. Any clinically significant abnormalities in laboratory test results in this patient population (including hepatic and renal panels, complete blood count, chemistry panel, serology and urinalysis) at screening or Day -1. 16. A history of acute clinically significant gastro-intestinal, musculoskeletal, endocrine, hematological, psychiatric, renal, hepatic, bronchopulmonary, neurological disease, acute venous thromboembolism within the last 3 months, a mechanical heart valve, acute stroke, transient ischaemic event (TIA) or acute myocardial infarction. 17. Creatinine Clearance of <60 mL/min (as estimated using Cockroft-Gault formula). This may be confirmed by urine creatinine clearance, the results of which will override the Cockroft-Gault estimated results. 18. Any other concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study. 19. Known history of clinically significant allergic hypersensitivity reactions or drug hypersensitivity (non-active hay fever is acceptable), including a known allergy to the study drug or to any of its components.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To investigate the effect of a 5-day treatment course with oseltamivir on the pharmacodynamics of warfarin in volunteers stabilized on warfarin;Secondary Objective: • To investigate the effect of a 5-day treatment course with oseltamivir on the steady state pharmacokinetics of warfarin (R and S forms) in volunteers stabilized on warfarin. • To investigate the single dose and steady state pharmacokinetics of oseltamivir and its carboxylate metabolite in the presence of warfarin in volunteers stabilized on warfarin. • To investigate the safety and tolerability of oseltamivir and warfarin when given concomitantly to volunteers stabilized on warfarin ;Primary end point(s): 1. Safety- The safety and adverse event data will be presented in individual listings, summary tables and graphs as appropriate. 2. Adverse Events - Adverse events will be listed and summarized at onset of adverse event. Body system and preferred terms within each body system will be summarized. All adverse events with all occurrences will be listed by subject. 3. Laboratory Safety Data - Clinical laboratory data will be listed by subject. Values outside the reference ranges will be highlighted and clinical significance stated. 4. Vital Signs - Vital sign measurements will be listed by subject. Plots of vital signs data will be provided. 5. Pharmacokinetics - Mixed model analyses will be used to estimate the effect of oseltamivir on warfarin PK parameters on day 5, and the effect of warfarin on oseltamivir PK parameters, and PK parameters of its carboxylate metabolite, on days 1 and 5. (For more information please refer to Protocol Synopsis, Statistical Considerations and Analytical Plan) 6. Pharmacodynamics - A mixed model analysis will be used to estimate the effect of oseltamivir on the INR, as measured from venous samples in volunteers stabilized on warfarin. (For more information please refer to Protocol Synopsis, Statistical Considerations and Analytica | — |
Countries
United Kingdom
Outcome results
None listed