Pharmacokinetics of Oseltamivir Carboxylate In Morbidly Obese Subjects

• Sponsor: Manjunath Prakash Pai (Other)
• Overall Status: Completed
• CT.gov ID: NCT01179919
• Collaborator: Hoffmann-La Roche (Industry)
• Enrollment: 21
• Location: 1
• Arm: 1
• Duration (Months): 5
• Patients Per Site Per Month: 4.2

Study Details

Study Description

Brief Summary

One in three Americans are obese. Obese subjects may or may not need higher doses of the anti-flu drug known as Tamiflu (oseltamivir). The current study is being done to see if the FDA approved dose of oseltamivir will achieve similar concentrations in obese healthy volunteers compared to that previously shown in non-obese volunteers.

Condition or Disease	Intervention/Treatment	Phase
Obesity	Drug: Oseltamivir	Phase 1/Phase 2

Detailed Description

The incidence of obesity has increased dramatically over the past two decades in the United States (US). Twenty-five percent of adult Americans are now classified as obese. Obesity is associated with physiological alterations that can affect drug clearance and volume of distribution. Obese subjects are often excluded from phase 1 pharmacokinetic studies. As a result, drug dosing regimens developed for clinical use may not be appropriate for the obese population. Use of fixed dosing regimens may result in under dosing of obese patients. In contrast adjustment of drug dosing based on total body weight may lead to over dosing of obese patients. Oseltamivir phosphate (Tamiflu®) is an antiviral agent that is currently dosed as 75 mg once daily for chemoprophylaxis and twice daily for treatment of influenza in adults.

Oseltamivir is rapidly converted to its active metabolite, oseltamivir carboxylate by esterases. The clearance of oseltamivir carboxylate is dependent on tubular secretion and glomerular filtration. Given that these drug elimination pathways may be enhanced in obese individuals, oseltamivir carboxylate plasma exposures may be lower in obese subjects compared to normal weight subjects. Although a specific plasma exposure target for oseltamivir carboxylate has not been established, lower oseltamivir carboxylate exposures may predispose obese patients to treatment failure and increase the probability for emergence of oseltamivir-resistant influenza virus. The current study proposes to characterize the plasma oseltamivir carboxylate concentration-time profile after multiple doses of oral oseltamivir in a cohort of healthy morbidly obese subjects. The study will be performed using a phase 1, open-label,multiple dose, pharmacokinetic study design in twenty obese adult subjects. This pilot study will provide pharmacokinetic data that may be incorporated into existing oseltamivir carboxylate population pharmacokinetic models to define appropriate doses of oseltamivir in obese patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Official Title: Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oseltamivir Dosed Group Oseltamivir 75 mg by mouth every 12 hours for 9 doses	Drug: Oseltamivir; Capsule, 75 mg by mouth for 9 doses; Other Names: Tamiflu

Outcome Measures

Primary Outcome Measures

1. Steady-State AUC of Oseltamivir Carboxylate [6 days]

   AUC is the area under the concentration-time curve. This is measured as concentration in nanograms of oseltamivir carboxylate per milliliter of plasma multiplied by time in hours (hour*ng/mL)

Secondary Outcome Measures

1. Steady-State Cmax and Cmin of Oseltamivir Carboxylate [6 days]

   Cmax is the maximum concentration and Cmin in the minimum concentration of oseltamivir carboxylate measured in nanogram of oseltamivir carboxylate per milliliter of plasma (ng/mL)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• males and females, 18 to 50 years of age

• non-smoking or light-smoking (≤5 cigarettes per day) volunteers

• BMI ≥ 40 kg/m2

• female subjects of childbearing potential either surgically sterilized, using an effective method of contraception (diaphragm, cervical cap,condom) or agree to abstain from sex from time of pre-study screening, during entire study period and 1 week following the study period.

Exclusion Criteria:

• history of significant hypersensitivity reaction to oseltamivir

• history of gastric bypass surgical procedure

• history of significant clinical illness requiring pharmacological management

• abnormal serum electrolyte or complete blood count requiring further clinical work-up

• transaminases (AST or ALT) >2.5 x upper limit of normal

• estimated creatinine clearance <50 mL/min (Cockcroft-Gault equation)

• positive urine pregnancy test (if female)

• abnormal electrocardiogram (ECG) as judged by study physician

• unable to tolerate venipuncture and multiple blood draws

• clinically significant abnormal physical examination defined as a physical finding requiring further clinical work-up

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	TKL Research	Paramaus	New Jersey	United States	07652

Sponsors and Collaborators

• Manjunath Prakash Pai
• Hoffmann-La Roche

Investigators

• Principal Investigator: Manjunath Pai, PharmD, ACPHS

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Manjunath Prakash Pai, Associate Professor, University of Michigan
• ClinicalTrials.gov Identifier: NCT01179919
• Other Study ID Numbers: 10-002
• First Posted: Aug 11, 2010
• Last Update Posted: Feb 9, 2017
• Last Verified: Dec 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Manjunath Prakash Pai, Associate Professor, University of Michigan: Oseltamivir; Obesity; Influenza; Pharmacokinetics in Obesity
• Additional relevant MeSH terms: Obesity; Oseltamivir

Study Results

Participant Flow

Arm/Group Title	Oseltamivir Dosed Group
Arm/Group Description	Oseltamivir 75 mg by mouth every 12 hours for 9 doses Oseltamivir: Capsule, 75 mg by mouth for 9 doses
Period Title: Overall Study
STARTED	21
COMPLETED	19
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Oseltamivir Dosed Group
Arm/Group Description	Oseltamivir 75 mg by mouth every 12 hours for 9 doses Oseltamivir: Capsule, 75 mg by mouth for 9 doses
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	36
Gender (Count of Participants)
Female	17 81%
Male	4 19%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 33.3%
White	11 52.4%
More than one race	3 14.3%
Unknown or Not Reported	0 0%
Body Mass Index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	43.7

Outcome Measures

1. Primary Outcome

Title	Steady-State AUC of Oseltamivir Carboxylate
Description	AUC is the area under the concentration-time curve. This is measured as concentration in nanograms of oseltamivir carboxylate per milliliter of plasma multiplied by time in hours (hour*ng/mL)
Time Frame	6 days

Outcome Measure Data

Analysis Population Description

Subjects who received all 9 doses of oseltamivir

Arm/Group Title	Oseltamivir Dosed Group
Arm/Group Description	Oseltamivir 75 mg by mouth every 12 hours for 9 doses Oseltamivir: Capsule, 75 mg by mouth for 9 doses
Measure Participants	19
Mean (Standard Deviation) [hour*ng/mL]	2579 (510)

2. Secondary Outcome

Title	Steady-State Cmax and Cmin of Oseltamivir Carboxylate
Description	Cmax is the maximum concentration and Cmin in the minimum concentration of oseltamivir carboxylate measured in nanogram of oseltamivir carboxylate per milliliter of plasma (ng/mL)
Time Frame	6 days

Outcome Measure Data

Analysis Population Description

Subjects who received all 9 doses of oseltamivir

Arm/Group Title	Oseltamivir Dosed Group
Arm/Group Description	Oseltamivir 75 mg by mouth every 12 hours for 9 doses Oseltamivir: Capsule, 75 mg by mouth for 9 doses
Measure Participants	19
Cmax	316 (68.1)
Cmin	113 (37.4)

Adverse Events

Time Frame	6 days
Arm/Group Title	Oseltamivir Dosed Group
Arm/Group Description	Oseltamivir 75 mg by mouth every 12 hours for 9 doses Oseltamivir: Capsule, 75 mg by mouth for 9 doses
All Cause Mortality
	Oseltamivir Dosed Group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Oseltamivir Dosed Group
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Other (Not Including Serious) Adverse Events
	Oseltamivir Dosed Group
	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)
General disorders
Anxiety	1/21 (4.8%)	1

Limitations/Caveats

This study only evaluated obese subjects. The concentrations measured in plasma may not reflect concentrations in tissues such as the lungs.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.