Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study

Francisco M Marty, Choy Y Man, Charles van der Horst, Bruno Francois, Denis Garot, Rafael Mánez, Visanu Thamlikitkul, José A Lorente, Francisco Alvarez-Lerma, David Brealey, Henry H Zhao, Steve Weller, Phillip J Yates, Amanda F Peppercorn, Francisco M Marty, Choy Y Man, Charles van der Horst, Bruno Francois, Denis Garot, Rafael Mánez, Visanu Thamlikitkul, José A Lorente, Francisco Alvarez-Lerma, David Brealey, Henry H Zhao, Steve Weller, Phillip J Yates, Amanda F Peppercorn

Abstract

Background: Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza.

Methods: Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed.

Results: One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1-11) a median of 4.5 days (range, 1-7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment.

Conclusions: Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir.

Clinical trials registration: NCT01014988.

Keywords: A/H1N1pdm09; Influenza; hospitalized; intravenous zanamivir; pandemic influenza; safety; zanamivir.

Figures

Figure 1.
Figure 1.
Median change from baseline influenza A or B viral load by quantitative real-time polymerase chain reaction in patients with positive baseline results; interquartile ranges are also shown.

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