90b. Safety, Tolerability and Pharmacokinetics (PK) of Intravenous Zanamivir (IVZ) Treatment in Hospitalized Pediatric and Adolescent Patients with Influenza: A Phase II Open-Label, Multicenter, Single- Arm Study
Session: Oral Abstract Session: PIDS Featured Oral Abstracts
Thursday, October 27, 2016: 10:45 AM
Room: 391-392
Background:  There is a critical unmet need for an effective parenteral anti-influenza (flu) treatment in children at high risk of complications and who cannot tolerate enteral therapy.  IVZ is a neuraminidase inhibitor in development for treatment of hospitalized patients with severe flu.

Methods:  Doses were selected to provide exposures comparable to 600 mg in adults. Hospitalized symptomatic pediatric patients with laboratory-confirmed flu presenting within 7 days of illness onset received IVZ for 5-10 days at 14 mg/kg (0.5 to <6 yrs of age), or 12 mg/kg not to exceed 600 mg (6 to <18 yrs) BID, adjusted for renal function.  Safety, PK, clinical outcomes, and virology were assessed for up to 23 days post-treatment.

Results:  71 patients with median age of 7 years (range, 0.6-17) from 5 countries were enrolled.  69% had received prior oseltamivir (median, 2 days), and 56% had chronic medical conditions. Median time from flu symptom onset to IVZ was 4 days (range, 0-7). At baseline 59% had an infiltrate on chest X-ray, 34% required mechanical ventilation, and 6% ECMO.  During the study 65% required ICU care. 14/28-day cumulative mortality was 4%/7%.

72% of patients experienced adverse events (AEs) and 21% had serious AEs (SAEs), including 5 deaths. No SAEs were identified by the investigator to be drug-related. There were no clinically significant findings in labs, vital signs, or ECGs. 

Mean serum zanamivir AUCs from 34 patients with normal renal function who received 12 mg/kg, 14 mg/kg, or 600 mg of IVZ ranged from 64.5 to 110 h*mg/mL and were generally consistent with that seen in adults (82.9 to 90.3 h*mg/mL).

For patients who were PCR+ for flu at baseline (77%), the change in viral load was similar for all subtypes (Figures 1 and 2).  A treatment emergent resistance substitution, E119G, was detected in a day 5 H1N1 isolate from an immunocompetent patient who improved clinically while on IVZ. No phenotype data were available as the sample could not be cultured.

Conclusion:  No pattern of AEs or SAEs attributable to IVZ were identified. Dose selection based on age, weight, and renal function provided exposure similar to adults, confirming an appropriate pediatric dosing regimen. IVZ may provide a suitable treatment option for children with severe flu. (ClinicalTrials.gov NCT01014988)

Jeffrey Blumer, MD, PhD1, John S. Bradley, MD, FIDSA, FPIDS2, Jose R. Romero, MD3, Marian Michaels, MD, MPH4, David W. Kimberlin, MD, FIDSA, FPIDS5, Go Yamamoto, MD6, Grace Roberts, MS7, Mohammad Hossain, PhD8, Denise Shortino, MS9, Phillip Yates, PhD10, Bryan Adams, PhD9 and Amanda Peppercorn, MD11, (1)Department of Pediatrics, University of Toledo, Toledo, OH, (2)Pediatric Infectious Diseases, Rady Children’s Hospital, University of California at San Diego School of Medicine, San Diego, CA, (3)University of Arkansas for Medical Sciences, Little Rock, AR, (4)Children's Hospital of Pittsburgh, Pittsburgh, PA, (5)Pediatrics, University of Alabama at Birmingham, Birmingham, AL, (6)Fukuoka Tokushukai Medical Center, Kasuga-city , Fukuoka, Japan, (7)GlaxoSmithKline, Research Triangle Park, NC, (8)GlaxoSmithKline, King of Prussia, PA, (9)PAREXEL, Durham, NC, (10)GlaxoSmithKline, Stevenage, United Kingdom, (11)GlaxoSmithKline, Cambridge, MA

Disclosures:

J. Blumer, GSK: Investigator , Research support

J. S. Bradley, None

J. R. Romero, GSK: Investigator , Research grant

M. Michaels, GSK: Research Contractor , institution not to me personally nor for my salary

D. W. Kimberlin, GSK: Investigator , I served as one of dozens of clinical trial sites for the GSK zanamivir study. All monies went to my university and not to me and Research grant

G. Yamamoto, None

G. Roberts, GSK: Employee and Shareholder , Salary

M. Hossain, GlaxoSmithKline: Employee and Shareholder , Salary

D. Shortino, GSK: Independent Contractor and Shareholder , PAREXEL employee

P. Yates, GSK: Employee , Salary and Shares

B. Adams, GSK: Employee of CRO and Shareholder , Salary as employee of CRO and Salary

A. Peppercorn, GSK: Employee and Shareholder , Salary

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