Pharmacokinetics of Oseltamivir Carboxylate In Morbidly Obese Subjects

Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults

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.

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Drug: Oseltamivir

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 Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Paramaus, New Jersey, United States, 07652
      • TKL Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	6 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	6 days

Collaborators and Investigators

• Sponsor: Manjunath Prakash Pai
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: Manjunath Pai, PharmD, ACPHS

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: August 10, 2010
• First Submitted That Met QC Criteria: August 10, 2010
• First Posted (Estimate): August 11, 2010

Study Record Updates

• Last Update Posted (Estimate): February 9, 2017
• Last Update Submitted That Met QC Criteria: December 16, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Obesity; Influenza; Oseltamivir; Pharmacokinetics in Obesity
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Oseltamivir
• Other Study ID Numbers: 10-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The summative data have been published and are available as open-access to the public: doi10.1128/AAC.00422-11