Obesity
Conditions
Keywords
Oseltamivir, Obesity, Influenza, Pharmacokinetics in Obesity
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.
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.
Interventions
DRUGOseltamivir
Capsule, 75 mg by mouth for 9 doses
Sponsors
Hoffmann-La Roche
Manjunath Prakash Pai
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oseltamivir Dosed Group Oseltamivir 75 mg by mouth every 12 hours for 9 doses
Oseltamivir: Capsule, 75 mg by mouth for 9 doses | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Oseltamivir Dosed Group |
|---|---|
| Age, Continuous | 36 years |
| Body Mass Index | 43.7 kg/m^2 |
| Gender Female | 17 Participants |
| Gender Male | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 21 |
| serious Total, serious adverse events | 0 / 21 |
Outcome results
Primary
Steady-State AUC of Oseltamivir Carboxylate
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
Population: Subjects who received all 9 doses of oseltamivir
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oseltamivir Dosed Group | Steady-State AUC of Oseltamivir Carboxylate | 2579 hour*ng/mL | Standard Deviation 510 |
Secondary
Steady-State Cmax and Cmin of Oseltamivir Carboxylate
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
Population: Subjects who received all 9 doses of oseltamivir
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oseltamivir Dosed Group | Steady-State Cmax and Cmin of Oseltamivir Carboxylate | Cmax | 316 ng/mL | Standard Deviation 68.1 |
| Oseltamivir Dosed Group | Steady-State Cmax and Cmin of Oseltamivir Carboxylate | Cmin | 113 ng/mL | Standard Deviation 37.4 |