1626. Safety, Tolerability and Pharmacokinetics (PK) of Intravenous Zanamivir (IVZ) Treatment in Hospitalized Adults with Influenza: A Phase 2 Open-Label, Multicenter, Single Arm Study
Session: Poster Abstract Session: Novel Antimicrobial Agents
Saturday, October 20, 2012
Room: SDCC Poster Hall F-H
Background: IVZ is a neuraminidase inhibitor in development for treatment of hospitalized patients with severe influenza.

Methods: Hospitalized symptomatic patients with local laboratory-confirmed influenza within 7 days of illness onset received IVZ for 5-10 days at 600 mg twice daily adjusted for renal impairment or renal replacement therapy (RRT). Patients were assessed during treatment and for 23 days after treatment for safety and virology. Serial serum PK sampling was done with the first and a repeat IVZ dose (ClinicalTrials.gov NCT01014988).

Results:  130 adults (56 female, 4 pregnant) from 8 countries were enrolled from November 2009 to August 2011. Median age was 48 years (range, 18-94), 75% were Caucasian, 33% were obese (BMI>30), 80% had received oseltamivir (median, 2 days).  75% had chronic medical conditions (respiratory 32%, immunocompromised 25%).  Median time from influenza symptom onset to IVZ was 4.5 days (range, 1-7). At baseline, 89% had an infiltrate on chest X-ray, 48% required mechanical ventilation (MV) and 5% RRT.  During the study 60% required MV, 83% required ICU care, and 3% ECMO.  Median hospital stay was 15 days (range, 1-133) and median ICU stay was 11.5 days (range, 1-104). 14 and 28-day cumulative mortality was 13% and 17%.

94% of subjects had influenza A (71% H1N1pdm09, 12% H3N2, 11% subtype unknown), 2% influenza B and 4% not typed. Of 93 subjects with positive baseline nasopharyngeal PCR, median baseline viral load was 5.34 log10 c/mL (range, 2.86-8.17) and median change at Day 3 was –1.42 log10 c/mL (range, –3.38 to +1.08). Steady state PK data from 76 subjects with normal renal function (mean Cmax=35.3 µg/mL, AUC=90.3 h*µg/mL, Cmin= 0.82 µg/mL) were as expected for 600 mg and above the mean reported influenza IC50 (0.08-1.01 ng/mL) for IVZ.

85% of subjects experienced adverse events (AEs), 44% had a grade 3 or 4 AE and 34% a serious AE. 13% met protocol defined liver-event criteria (8% on-treatment, 5% post-treatment) with no correlation to PK. There were no clinically significant trends in labs, vital signs or ECGs. Potential causality of AEs was confounded by severity of illness and concomitant medications.  

Conclusion:  No significant safety signals attributable to IVZ were identified in this population with severe influenza.  A Phase 3 study of IVZ is underway.

Visanu Thamlikitkul, MD1, Francisco Marty, MD2,3,4, Choy Man, BSc5, Henry Zhao, PhD5, Stephen Weller, MS6, Phillip Yates, PhD7, Charles van der Horst, MD8, Denis Garot, MD9, Bruno Francois, MD10, Michael Parry, MD11, Raphael Manez, MD12, Erica Bullock, BA13 and Amanda Peppercorn, MD6, (1)Siriraj Hospital, Mahidol University, Bangkok, Thailand, (2)Brigham and Women's Hospital, Boston, MA, (3)Harvard Medical School, Boston, MA, (4)Dana-Farber Cancer Institute, Boston, MA, (5)GlaxoSmithKline, Research Triangle Park, NC, (6)GlaxoSmithKline, Inc, Research Triangle Park, NC, (7)GSK, Stevenage, United Kingdom, (8)Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, (9)Hopital Bretonneau, Tours, France, (10)ICU/CIC-08O1 Inserm, Hopital Dupuytren, Limoges, France, (11)Stamford Hospital, Stamford, CT, (12)Hospital Unversario de Belvitge, Barcelona, Spain, (13)Glaxosmithkline, Research Triangle Park, NC

Disclosures:

V. Thamlikitkul, Glaxosmithkline: Investigator, Consulting fee and Research grant

F. Marty, Glaxosmithkline: Investigator, Consulting fee

C. Man, Glaxosmithkline: Employee, Salary

H. Zhao, Glaxosmithkline: Employee, Salary

S. Weller, Glaxosmithkline: Employee, Salary

P. Yates, Glaxosmithkline: Employee, Salary

C. van der Horst, None

D. Garot, None

B. Francois, Glaxosmithkline: Consultant, Consulting fee

M. Parry, None

R. Manez, None

E. Bullock, Glaxosmithkline: Employee, Salary

A. Peppercorn, Glaxosmithkline: Employee, Salary

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