Pharmacokinetic Study of Oseltamivir and Intravenous Zanamivir in Healthy Adults - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator:	Johns Hopkins Bloomberg School of Public Health
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00921726

Purpose

Due in part to widespread availability of oseltamivir and clinical experience using oseltamivir to treat H5N1 influenza virus infections, many strains of influenza have become resistant to it. Other reliable methods of treating H5N1 must be identified in case of a pandemic. One such option is intravenous zanamivir used in combination with oseltamivir. The primary purpose of this study is to evaluate the interaction between oral oseltamivir and intravenous zanamivir administered as either a continuous or intermittent infusion in healthy adults.

Condition	Intervention	Phase
Influenza Virus Diseases	Drug: Zanamivir Drug: Oseltamivir	Phase I

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Crossover Assignment, Pharmacokinetics Study
Official Title:	Phase 1, Open-Label Study to Evaluate Potential Pharmacokinetic Interactions Between Orally-Administered Oseltamivir and Intravenous Zanamivir in Healthy Thai Adult Subjects

Resource links provided by NLM:

MedlinePlus related topics: Flu

Drug Information available for: Zanamivir Oseltamivir Tamiflu

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Oseltamivir carboxylate Cmax and AUC (0-12) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Zanamivir Cmax and AUC (0-12) for continuous infusion and Zanamivir Cmax, AUC (-12), and C12 for intermittent infusions [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Oseltamivir Cmax, AUC (0-12), and C12 [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Oseltamivir carboxylate AUC (0-24), C12, delta-z, and t(1/2) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Estimated Enrollment:	16
Study Start Date:	July 2009
Estimated Primary Completion Date:	May 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Participants will receive treatment in the following order: Study Regimens A, B, C, D	Drug: Zanamivir Continuous (800 mg in Regimen A, 3600 mg in Regimen C) and intermittent (3600 mg in Regimen D) infusion Drug: Oseltamivir 150 mg oral tablets taken five times over 3 days in Regimens A, B, C, and D
2: Experimental Participants will receive treatment in the following order: Study Regimens B, A, C, D	Drug: Zanamivir Continuous (800 mg in Regimen A, 3600 mg in Regimen C) and intermittent (3600 mg in Regimen D) infusion Drug: Oseltamivir 150 mg oral tablets taken five times over 3 days in Regimens A, B, C, and D

Detailed Description:

It is very likely that during an influenza pandemic, intravenous zanamivir will be used in combination with oseltamivir. Although the potential for a drug interaction between the two drugs is very low, the likelihood of coadministration combined with the common route of renal clearance of both drugs and the current lack of information on the organic anion transporter polypeptides (OATP) inhibition potential of zanamivir in vivo warrants verification of a lack of an interaction. This study will provide clinical guidance for the use of intravenous zanamivir in settings where oral oseltamivir is commonly used, such as areas in which human cases of H5N1 have been reported.

The total duration of study participation is approximately 13 weeks. Each participant will have a screening visit, four treatment steps, and a follow-up visit. The screening visit to determine enrollment eligibility will be conducted within 45 days prior to receiving the first dose. Participants will be randomized to receive either Regimen A or B for Step 1. Participants who received Regimen A will receive Regimen B in Step 2 and vice versa. After completing Step 2, all participants will continue with Regimens C and D, consecutively, in Steps 3 and 4, with at least 3 days between each step. A follow-up visit will occur 7-10 days after completing the last treatment assessments or withdrawing from the study.

Regimen A consists of continuous intravenous zanamivir infusion (800 mg) for 16 hours. Regimen B consists of 150 mg oral oseltamivir tablets taken five times over 3 days. Regimen C consists of 150 mg oral oseltamivir tablets taken five times over 3 days plus continuous intravenous zanamivir infusion (3600 mg) for 36 hours. Regimen D consists of 150 mg oral oseltamivir tablets taken five times over 3 days plus intermittent intravenous zanamivir infusion received in five 30 minute intervals (3000 mg total).

Blood and urine collection, vital signs, pharmacokinetic sampling, adverse event assessment, and pregnancy test for females will occur at each step in the study. The follow-up visit will involve blood and urine collection, vital signs, adverse event assessment, and pregnancy test for females.

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Good general health
Body mass index between 17 - 32 kg/m^2
Body weight of at least 37 kg
Able to read, comprehend, and write at a sufficient level to complete study-related materials
Normal ECG with QTC less than 450 msec as judged by cardiologist
Willing and ability to comply with the study protocol for the duration of the trial

Exclusion Criteria:

History of cardiac disease or abnormality. More information on this criterion can be found in the protocol.
Family history of sudden cardiac death
HIV-infected
Hepatitis C virus infected
Positive for hepatitis B surface antigen (HBsAg)
History of renal disease, hepatic disease, and/or cholecystectomy
Evidence of active substance abuse
History of alcohol or substance abuse or dependence within 6 months prior to study entry. More information on this criterion can be found in the protocol.
Use of prescription or non-prescription drugs, except paracetamol, at doses of up to 2 g/day. More information on this criterion can be found in the protocol.
Use of FluMist, inactivated influenza vaccine, or any other anti-influenza antiviral medications within 14 days prior to study entry
Participated in a clinical trial and received a drug or new chemical entity within 30 days or five half-lives prior to study entry.
Unwilling to abstain from ingesting alcohol within 48 hours prior to study entry until collection of the final pharmacokinetic sample during each period
Donated blood to the extent that participation in this study would result in excess of 300 mL donated within a 30 day period
History of allergy to the study drug or drugs of this class. More information on this criterion can be found in the protocol.
Unstable medical condition that, in the opinion of the investigator, would interfere with the study
Anyone that, in the opinion of the investigator, has a risk of non-compliance with study procedures
AST or ALN of at least 1.5 ULN
Certain abnormal laboratory values
Agree to use effective methods of birth control. More information on this criterion can be found in the protocol.
Pregnant or breastfeeding

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00921726

Locations

Thailand
Mathidol University
Salaya, Thailand, 73170

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Johns Hopkins Bloomberg School of Public Health

Investigators

Principal Investigator:

Sasithon Pukrittayakamee, MD

Mathidol University, Thailand

More Information

Publications:

Beigel J, Bray M. Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102. Epub 2008 Feb 4. Review.

Hata K, Koseki K, Yamaguchi K, Moriya S, Suzuki Y, Yingsakmongkon S, Hirai G, Sodeoka M, von Itzstein M, Miyagi T. Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. Antimicrob Agents Chemother. 2008 Oct;52(10):3484-91. Epub 2008 Aug 11.

Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, Nicholson K. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation. Health Technol Assess. 2009 Feb;13(11):iii, ix-xii, 1-246. Review.

Responsible Party:	Mathidol University, Thailand ( Sasithon Pukrittayakamee, MD )
Study ID Numbers:	SEA 003
Study First Received:	June 12, 2009
Last Updated:	December 1, 2009
ClinicalTrials.gov Identifier:	NCT00921726 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Drug Interaction

Additional relevant MeSH terms:

Anti-Infective Agents
RNA Virus Infections
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Orthomyxoviridae Infections
Zanamivir
Antiviral Agents

Pharmacologic Actions
Oseltamivir
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Therapeutic Uses
Influenza, Human

ClinicalTrials.gov processed this record on February 08, 2010