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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02717754

Enrollment

Registered

2016-03-24

Start date

2009-12-31

Completion date

2010-05-31

Last updated

2016-06-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteer

Brief summary

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.

Interventions

DRUGOseltamivir

Oseltamivir will be administered at 100 or 200 mg intravenous BID for 5 days.

DRUGPlacebo

Oseltamivir matched placebo will be administered intravenous for 5 days.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 45 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Oseltamivir and RO0640802	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5	AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time to Reach Maximum Plasma Concentration (Tmax) of Oseltamivir and RO0640802	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5	Tmax is time of observed maximum plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Half-Life (t1/2) of Oseltamivir and RO0640802	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5	t1/2 is the time measured for the plasma concentration to decrease by one half. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Cmax of Oseltamivir and RO0640802	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1	Cmax is the maximum observed plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Clearance (CL) of Oseltamivir and RO0640802	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5	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.
Minimum Plasma Concentration (Cmin) of RO0640802	12-hour post dose on Day 1, 5 and predose on Day 2, 3, 4, 5	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.
Volume of Distribution (Vd) of Oseltamivir and RO0640802	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5	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.
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Oseltamivir and RO0640802	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1	AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

Countries

United States

Participant flow

Recruitment details

In total 99 participants were included in study, but as first 50 participants were administered infusion incorrectly thus only 49 participants were considered evaluable for pharmacokinetics. The 50 participants were reported for safety under arm groups placebo (incorrect infusion duration), oseltamivir 100 or 200 mg (incorrect infusion duration).

Participants by arm

Arm	Count
Placebo Participants received oseltamivir matched placebo BID for 5 days.	10
Oseltamivir 100 mg Participants received 100 mg oseltamivir intravenous BID for 5 days.	19
Oseltamivir 200 mg Participants received 200 mg oseltamivir intravenous BID for 5 days.	20
Placebo (Incorrect Infusion Duration) Participants were randomized to receive oseltamivir matched placebo intravenous BID for 5 days but received incorrect infusion duration.	10
Oseltamivir 100 mg (Incorrect Infusion Duration) Participants were randomized to receive oseltamivir 100 mg intravenous BID for 5 days but received incorrect infusion duration.	20
Oseltamivir 200 mg (Incorrect Infusion Duration) Participants were randomized to receive oseltamivir 200 mg intravenous BID for 5 days but received incorrect infusion duration.	20
Total	99

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Incorrect Infusion Duration	0	0	0	10	20	20

Baseline characteristics

Characteristic	Placebo	Oseltamivir 100 mg	Oseltamivir 200 mg	Placebo (Incorrect Infusion Duration)	Oseltamivir 100 mg (Incorrect Infusion Duration)	Oseltamivir 200 mg (Incorrect Infusion Duration)	Total
Age, Continuous	28.1 years STANDARD_DEVIATION 6.19	28.3 years STANDARD_DEVIATION 6.97	30.2 years STANDARD_DEVIATION 7.73	29.7 years STANDARD_DEVIATION 7.9	31.1 years STANDARD_DEVIATION 7.8	28.6 years STANDARD_DEVIATION 8.09	29.4040 years STANDARD_DEVIATION 7.44904
Sex: Female, Male Female	5 Participants	10 Participants	4 Participants	1 Participants	3 Participants	4 Participants	27 Participants
Sex: Female, Male Male	5 Participants	9 Participants	16 Participants	9 Participants	17 Participants	16 Participants	72 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	7 / 10	17 / 19	20 / 20	2 / 10	8 / 20	13 / 20
serious Total, serious adverse events	0 / 10	0 / 19	0 / 20	0 / 10	0 / 20	0 / 20

Outcome results

Primary

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.

Time frame: Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5

Population: Pharmacokinetic (PK) analysis population included all participants who were dosed correctly. Only participants who received oseltamivir were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Oseltamivir 100 mg	Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hour (AUC0-12h) of Oseltamivir and RO0640802 at Steady State	Oseltamivir	581 ng*hour/mL	Standard Deviation 178
Oseltamivir 100 mg	Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hour (AUC0-12h) of Oseltamivir and RO0640802 at Steady State	RO0640802	4147 ng*hour/mL	Standard Deviation 742
Oseltamivir 200 mg	Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hour (AUC0-12h) of Oseltamivir and RO0640802 at Steady State	Oseltamivir	1143 ng*hour/mL	Standard Deviation 178
Oseltamivir 200 mg	Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hour (AUC0-12h) of Oseltamivir and RO0640802 at Steady State	RO0640802	7966 ng*hour/mL	Standard Deviation 1427

Primary

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.

Time frame: Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5