Pharmacokinetics of Oseltamivir Carboxylate In Morbidly Obese Subjects

Phase 1

Completed

Conditions: Obesity

Interventions: Drug: Oseltamivir

Registration Number: NCT01179919

Lead Sponsor: Manjunath Prakash Pai

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Oseltamivir Dosed Group	Oseltamivir	Oseltamivir 75 mg by mouth every 12 hours for 9 doses

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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)