A Pharmacokinetic Study on Co-administration of Tamiflu (Oseltamivir) and Rimantadine in Healthy Volunteers

Study Overview
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Brief Summary
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This open label, randomized, three-period crossover study will evaluate the effect of co-administration of Tamiflu (oseltamivir) and rimantadine on the pharmacokinetics of Tamiflu and rimantadine. Healthy volunteers will receive multiple oral doses of Tamiflu, rimantadine or Tamiflu plus rimantadine in random order, with a minimum wash-out period of 7 days between treatments. Anticipated time on study is up to 11 weeks.

Official Title
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An Open-label, Multiple Dose, Randomized, Three-period Crossover Study in Healthy Subjects to Evaluate the Effect of Co-administration of Oseltamivir (Ro 64-0796) 75 mg Twice Daily and Rimantadine 100 mg Twice Daily on the Pharmacokinetic Properties of Oseltamivir and Rimantadine.

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Drug: oseltamivir [Tamiflu]
* Drug: rimantadine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults, aged 18 to 45 years Healthy as judged by general physical examination, medical history, vital signs, 12-lead ECG and laboratory tests Body Mass Index (BMI) 18-34 kg/m2 Willing not to participate in any other trial including an investigational drug for 3 months following the last dose Male subjects must agree to use a barrier contraception during the study and for 3 months after discontinuation of treatment Female subjects of non-child bearing potential or under effective contraception who are either post-menopausal, surgically sterile, or who agree to use barrier contraception during the whole study in addition to an intrauterine device or hormonal contraception for at least 3 months prior to 1st dose, during the study and for 3 months after discontinuation of treatment Exclusion Criteria: History of or current clinically significant disease or disorder Positive Hepatitis B, Hepatitis C, HIV 1 or 2 test result Positive pregnancy test or lactating women Clinically relevant history of allergy or hypersensitivity Clinically relevant history of abuse of alcohol or other drugs; tobacco smoking is allowed (</= 10 cigarettes a day or equivalent of tobacco in cigars or pipe) Any major illness within 30 days prior to screening examination Administration of any medication during the 7 days prior to drug administration, except for paracetamol and aspirin (up to 48 hours before first dose) and oral contraceptives Participation in a clinical study with an investigational drug within 3 months prior to study day 1 Donation or loss of more than 500 mL of blood within the 3 months prior to study day 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br> | Drug: oseltamivir [Tamiflu]<br>* multiple oral doses<br>|
| Active Comparator: B<br> | Drug: rimantadine<br>* multiple oral doses<br>|
| Experimental: C<br> | Drug: oseltamivir [Tamiflu]<br>* multiple oral doses<br>Drug: rimantadine<br>* multiple oral doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir carboxylate is active metabolite of oseltamivir. AUC0-12 of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine, using the linear trapezoidal rule. | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | 
| Steady State Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours After Dosing (AUC0-12) of Rimantadine | AUC0-12 of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir, using the linear trapezoidal rule. | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate | Oseltamivir carboxylate is active metabolite of oseltamivir. Cmax of oseltamivir and oseltamivir carboxylate were calculated following the administration of oseltamivir alone or in combination with rimantadine and was directly observed from the data. | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | 
| Maximum Plasma Concentration (Cmax) of Rimantadine | Cmax of rimantadine was calculated following the administration of rimantadine alone or in combination with oseltamivir and was directly observed from the data. | Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 5 | 
| Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. | Up to 11 weeks | 
| Number of Participants With Abnormal Vital Signs | Vital signs included heart rate (HR), blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), and body temperature. Blood pressure and pulse rate were recorded when participants were rested in a supine position for at least 5 minutes and after standing for 2 minutes. Vital signs values that fall outside the investigator's normal ranges were recorded. | Screening (Days -28 to -2); pre-dose and 2h post-dose on D1 and D5 of each treatment period; at Follow-up visit (10 -14 days after last dose) for blood pressure and HR; Screening; Day -1 of each treatment period; Follow-up visit for temperature | 
| Number of Participants With Marked Abnormality in Laboratory Parameters | Laboratory analysis included hematology (hemoglobin, hematocrit, erythrocytes, platelets counts, leukocytes counts, neutrophils, eosinophils, lymphocytes, basophils, and monocytes);, biochemistry (aspartate aminotransferase , alanine aminotransferase, gamma glutamyl trans peptidase, total bilirubin, alkaline phosphatase, lactate dehydrogenase, albumin, creatinine, urea, creatine phosphokinase, total protein, sodium, chloride, calcium, phosphate, potassium, glucose (fasting), amylase, lipase, total cholesterol, and calculated creatinine clearance); and urinalysis. Marked laboratory test values (high and low) falling outside the marked reference range and which also represents a clinically relevant change from baseline of at least a designated amount were recoded. In this study, marked abnormality ranges for phosphate as 0.75 - 1.60 millimole (mmol)/L and proteinuria (0 to 4+, and 1). | Screening; Day -1 and Day 5 (pre-dose) of each treatment period; Follow-up visit | 
| Number of Participants With Clinically Significant or Treatment Related Changes in Electrocardiogram (ECG) | ECG was recorded when participants were rested in a supine position for at least 5 minutes. | Screening; pre-dose on Day 1 and Day 5 of each treatment period; Follow-up visit |