A Study to Investigate the Safety, Tolerability, and Pharmacokinetics (PK) of Oseltamivir and Its Carboxylate Metabolite, RO0640802 in Healthy Participants

Study Overview
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Brief Summary
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This multi-center, randomized, double-blind, multiple-dose, placebo-controlled, parallel-group study will assess the safety and PK of oseltamivir (Tamiflu) and its carboxylate metabolite, RO0640802 in healthy participants. Participants will be randomized to receive 100 milligrams (mg) oseltamivir, 200 mg oseltamivir, or placebo, all administered intravenously twice daily (BID). The anticipated time on study treatment is 5 days.

Official Title
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A Multiple-Center, Randomized, Double-blind, Multiple-Dose, Placebo-Controlled, Parallel-Group Study to Investigate the Safety, Tolerability, and Pharmacokinetics of RO0640796 (Oseltamivir) and Its Carboxylate Metabolite, RO0640802, Following Intravenous Administrations in Healthy Subjects

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Drug: Oseltamivir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with Body Mass Index (BMI) 18-34 kilograms per meter square (kg/m^2), inclusive Male participants who are willing to use barrier contraception for the duration of the study and for 3 months following the end of treatment Female participants who are of non-child bearing potential Female participants who are of child bearing potential utilizing two effective methods of contraception for the duration of the study and for 3 months following the end of treatment Exclusion Criteria: Evidence of clinically significant disease or disorder (for example, renal, cardiac, bronchopulmonary) Any other condition or disease which would place the participant at undue risk, or interfere with the assessment, or with the ability of the participant to complete the study Clinically significant orthostatic hypotension present at screening or history of clinically significant hypotensive episodes or symptoms of fainting, dizziness, or lightheadedness. Participants with abnormal electrocardiogram (ECG), bradycardia or mean QTc at screening Positive result for Hepatitis B, Hepatitis C, human immunodeficiency virus (HIV) 1 or 2 at screening Renal impairment Transplant recipients A known clinically relevant history of allergy or hypersensitivity Any clinically relevant abnormal laboratory test results A clinically relevant history of abuse of alcohol or other drugs of abuse Any major illness within 30 days prior to the screening examination Smoking of more than 10 cigarettes a day or an equivalent amount of tobacco in the form of cigars or pipe Participation in a clinical study with an investigational drug within 3 months prior to Day 1 Donation/loss of more than 500 milliliters (mL) of blood within 3 months prior to Day 1 Positive pregnancy test at screening or Day -1 and lactating women

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oseltamivir 100 mg<br>Participants will receive 100 mg oseltamivir intravenous BID for 5 days. | Drug: Oseltamivir<br>* Oseltamivir will be administered at 100 or 200 mg intravenous BID for 5 days.<br>* Other names: Tamiflu, RO0640796;|
| Experimental: Oseltamivir 200 mg<br>Participants will receive 200 mg oseltamivir intravenous BID for 5 days. | Drug: Oseltamivir<br>* Oseltamivir will be administered at 100 or 200 mg intravenous BID for 5 days.<br>* Other names: Tamiflu, RO0640796;|
| Placebo Comparator: Placebo<br>Participants will receive oseltamivir matched placebo intravenous BID for 5 days. | Drug: Placebo<br>* Oseltamivir matched placebo will be administered intravenous for 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hour (AUC0-12h) of Oseltamivir and RO0640802 at Steady State | AUC is a measure of the plasma concentration of the drug over time. AUC is presented in nanogram times (*) hour per milliliter (ng*hour/mL). RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5 | 
| Maximum Plasma Concentration (Cmax) of Oseltamivir and RO0640802 at Steady State | Cmax is the maximum observed plasma concentration, presented in nanogram per milliliter (ng/mL). RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Oseltamivir and RO0640802 | AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 | 
| Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Oseltamivir and RO0640802 | AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5 | 
| Cmax of Oseltamivir and RO0640802 | Cmax is the maximum observed plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Oseltamivir and RO0640802 | Tmax is time of observed maximum plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5 | 
| Half-Life (t1/2) of Oseltamivir and RO0640802 | t1/2 is the time measured for the plasma concentration to decrease by one half. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5 | 
| Volume of Distribution (Vd) of Oseltamivir and RO0640802 | Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5 | 
| Clearance (CL) of Oseltamivir and RO0640802 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5 | 
| Minimum Plasma Concentration (Cmin) of RO0640802 | Collection of the 12-hour post-dose sample took place prior to administration of the second daily dose of drug. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir. | 12-hour post dose on Day 1, 5 and predose on Day 2, 3, 4, 5 |