Pharmacokinetic Study of Oseltamivir and Intravenous Zanamivir in Healthy Adults

Influenza Clinical Trial

Official title:

Phase 1, Open-Label Study to Evaluate Potential Pharmacokinetic Interactions Between Orally-Administered Oseltamivir and Intravenous Zanamivir in Healthy Thai Adult Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00921726
• Other study ID #: SEA 003
• Status: Completed
• Phase: Phase 1
• First received: June 12, 2009
• Last updated: March 18, 2010
• Start date: July 2009
• Est. completion date: October 2009

Study information

• Verified date: May 2009
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: October 2009
• Est. primary completion date: October 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Influenza
• Virus Diseases

Intervention

Drug:
• Zanamivir
Continuous (800 mg in Regimen A, 3600 mg in Regimen C) and intermittent (3600 mg in Regimen D) infusion
• Oseltamivir
150 mg oral tablets taken five times over 3 days in Regimens A, B, C, and D

Locations

Country	Name	City	State
Thailand	Mathidol University	Salaya

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Johns Hopkins Bloomberg School of Public Health

Country where clinical trial is conducted

Thailand, 

References & Publications (3)

Beigel J, Bray M. Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102. doi: 10.1016/j.antiviral.2008.01.003. Epub 2008 Feb 4. Review. — View Citation

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. doi: 10.1128/AAC.00344-08. Epub 2008 Aug 11. — View Citation

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. doi: 10.3310/hta13110. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Oseltamivir carboxylate Cmax and AUC (0-12)		Throughout study	No
Secondary	Zanamivir Cmax and AUC (0-12) for continuous infusion and Zanamivir Cmax, AUC (-12), and C12 for intermittent infusions		Throughout study	No
Secondary	Oseltamivir Cmax, AUC (0-12), and C12		Throughout study	No
Secondary	Oseltamivir carboxylate AUC (0-24), C12, delta-z, and t(1/2)		Throughout study	No