tetano
Editor, Senior Moderator
Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study
Francisco M. Marty1,
Choy Y. Man2,
Charles van der Horst3,
Bruno Francois4,
Denis Garot5,
Rafael M?ňez6,
Visanu Thamlikitkul7,
Jos? A. Lorente8,
Francisco ?lvarez-Lerma9,
David Brealey10,
Henry H. Zhao11,
Steve Weller12,
Phillip J. Yates13 and
Amanda F. Peppercorn2
+ Author Affiliations
1Division of Infectious Diseases, Brigham and Women's Hospital, Boston MA 02115, USA
2Clinical Development, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA
3School of Medicine, UNC Center for AIDS Research, Chapel Hill, NC 27514, USA
4ICU CHU Dupuytren, Inserm CIC 0801 and U 1092, Limoges 87042, France
5Service de r?animation m?dicale, H?pital Bretonneau, Tours 37044, France
6Intensive Care Medicine, Hospital Universitario de Bellvitge, Barcelona 8907, Spain
7Faculty of Medicine Siriraj Hospital, Mahidol Universtity, Bangkok 10700, Thailand
8Department of Critical Care, Hospital Universitario de Getafe, CIBERES, and Universidad Europea de Madrid, Madrid 28905, Spain
9Service of Intensive Care Medicine, Hospital Parc de Salut Mar, Barcelona 08003, Spain
10Anaesthesia and Critical Care, University College Hospital, London NW1 2BU, UK
11Clinical Statistics, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA
12Clinical Pharmacokinetics, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA
13Clinical Virology, GlaxoSmithKline Research and Development, Stevenage, UK
Corresponding author: Francisco M. Marty, MD, SM. Division of Infectious Diseases, Brigham and Women's Hospital, 75 Francis Street, PBB-A4, Boston, MA 02115, Tel: +1 617 525 8418, Fax:+1 617 732 6829, email: fmarty@partners.org
Alternate Corresponding author: Amanda F. Peppercorn, MD, Discovery Medicine, Antiviral DPU, GlaxoSmithKline, 5 Moore Drive, Mailbox 5.3743.3C, RTP, NC 27709, Tel: +1 919 483 7903, Fax:+1 919 315 6393, email: Amanda.f.peppercorn@gsk.com
Abstract
Background. Intravenous zanamivir (IVZ) is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza.
Methods. Patients were treated with IVZ 600 mg twice-daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, virus load and disease course were also assessed.
Results. One-hundred-thirty patients received IVZ (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 (SAEs) were reported in 85% and 34% of patients. SAEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis/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 was 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 PCR showed a median decrease in virus load of 1.42 log10 copies/mL after 2 days of treatment.
Conclusions. Safety, pharmacokinetic and clinical outcome data support further investigation of IV zanamivir.
http://jid.oxfordjournals.org/content/early/2013/08/26/infdis.jit467.abstract
Francisco M. Marty1,
Choy Y. Man2,
Charles van der Horst3,
Bruno Francois4,
Denis Garot5,
Rafael M?ňez6,
Visanu Thamlikitkul7,
Jos? A. Lorente8,
Francisco ?lvarez-Lerma9,
David Brealey10,
Henry H. Zhao11,
Steve Weller12,
Phillip J. Yates13 and
Amanda F. Peppercorn2
+ Author Affiliations
1Division of Infectious Diseases, Brigham and Women's Hospital, Boston MA 02115, USA
2Clinical Development, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA
3School of Medicine, UNC Center for AIDS Research, Chapel Hill, NC 27514, USA
4ICU CHU Dupuytren, Inserm CIC 0801 and U 1092, Limoges 87042, France
5Service de r?animation m?dicale, H?pital Bretonneau, Tours 37044, France
6Intensive Care Medicine, Hospital Universitario de Bellvitge, Barcelona 8907, Spain
7Faculty of Medicine Siriraj Hospital, Mahidol Universtity, Bangkok 10700, Thailand
8Department of Critical Care, Hospital Universitario de Getafe, CIBERES, and Universidad Europea de Madrid, Madrid 28905, Spain
9Service of Intensive Care Medicine, Hospital Parc de Salut Mar, Barcelona 08003, Spain
10Anaesthesia and Critical Care, University College Hospital, London NW1 2BU, UK
11Clinical Statistics, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA
12Clinical Pharmacokinetics, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA
13Clinical Virology, GlaxoSmithKline Research and Development, Stevenage, UK
Corresponding author: Francisco M. Marty, MD, SM. Division of Infectious Diseases, Brigham and Women's Hospital, 75 Francis Street, PBB-A4, Boston, MA 02115, Tel: +1 617 525 8418, Fax:+1 617 732 6829, email: fmarty@partners.org
Alternate Corresponding author: Amanda F. Peppercorn, MD, Discovery Medicine, Antiviral DPU, GlaxoSmithKline, 5 Moore Drive, Mailbox 5.3743.3C, RTP, NC 27709, Tel: +1 919 483 7903, Fax:+1 919 315 6393, email: Amanda.f.peppercorn@gsk.com
Abstract
Background. Intravenous zanamivir (IVZ) is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza.
Methods. Patients were treated with IVZ 600 mg twice-daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, virus load and disease course were also assessed.
Results. One-hundred-thirty patients received IVZ (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 (SAEs) were reported in 85% and 34% of patients. SAEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis/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 was 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 PCR showed a median decrease in virus load of 1.42 log10 copies/mL after 2 days of treatment.
Conclusions. Safety, pharmacokinetic and clinical outcome data support further investigation of IV zanamivir.
http://jid.oxfordjournals.org/content/early/2013/08/26/infdis.jit467.abstract