Pharmacokinetic Study of Oseltamivir and Intravenous Zanamivir in Healthy Adults

Overview

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.

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.