Clinical trial NCT01179919: Pharmacokinetics of Oseltamivir Carboxylate In Morbidly Obese Subjects
Official title: Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Obesity
Keywords: Oseltamivir
Obesity
Influenza
Pharmacokinetics in Obesity
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2010-08-11
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP

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.

Eligibility criteria: 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

Primary outcomes:
measure: Steady-State AUC of Oseltamivir Carboxylate
timeFrame: 6 days
Secondary outcomes:
measure: Steady-State Cmax and Cmin of Oseltamivir Carboxylate
timeFrame: 6 days
Other outcomes:
Locations:
city: Paramaus
country: United States
facility: TKL Research
state: New Jersey
Study officials:
affiliation: ACPHS
name: Manjunath Pai, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pai MP, Lodise TP Jr. Oseltamivir and oseltamivir carboxylate pharmacokinetics in obese adults: dose modification for weight is not necessary. Antimicrob Agents Chemother. 2011 Dec;55(12):5640-5. doi: 10.1128/AAC.00422-11. Epub 2011 Sep 19.