Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Intravenous Peramivir in Children With Influenza

Infants and young children are at greatest risk of mortality from epidemic influenza.
Influenza medications currently approved for use in the United States are administered
orally or via inhalation. Availability of a parenteral influenza medication could be of
great importance in medical and public health responses to both seasonal and pandemic
influenza. Peramivir is an experimental parenteral influenza drug that is in advanced stages
of clinical development. The primary objective of this study is to define the
pharmacokinetics (PK) of peramivir in children with confirmed influenza. The secondary
objectives are to: assess the safety and tolerability of intravenous (IV) peramivir in
children with influenza; assess viral dynamics as a function of drug PK; and assess virus
susceptibility to peramivir. This study is a prospective, open-label, age-stratified
PK/pharmacodynamic (PD) and safety evaluation of investigational IV peramivir in
hospitalized children with influenza infection who are unable to receive or have failed at
least three days oseltamivir or zanamivir therapy. A minimum of 63 children with confirmed
influenza will be enrolled into 1 of 7 age cohorts: Cohort I (>= 12 years to < 18 years);
Cohort II (>= 6 years to < 12 years); Cohort III (>= 2 years to < 6 years); Cohort IV (>=
181 days to < 2 years); Cohort V (>= 91 days to < 181 days); Cohort VI (>= 31 days to < 91
days) and Cohort VII (Birth to < 31 days). Only hospitalized children will be enrolled. At
study onset, Cohorts I, II and III (children from >=2 years to < 18 years of age) will be
enrolled initially. When PK and safety data from 9 total subjects enrolled Cohort I, Cohort
II and/or Cohort IIII are available and reviewed by the study's Data and Safety Monitoring
Board (DSMB), Cohorts IV-VII will be opened for enrollment. The initial doses selected for
use were based on modeling and from a recently completed clinical trial study of a fixed
dose (10 mg/kg) of peramivir in pediatric patients with influenza. In the current study,
PK data will be obtained in a real time basis, and doses in each cohort may be modified if
the target exposure [area under the curve (AUC) 24] falls outside of a pre-specified range.
Additional enrollments may be allowed if the dose requires modification in a given cohort.
In the event of a public health emergency, the National Institutes of Health (NIH), DSMB, or
Food and Drug Administration (FDA) may that all cohorts be open for enrollment. Subjects
will receive IV Peramivir once daily for 5 days or until the day of hospital discharge,
whichever comes first, and PK blood draws will be obtained around the second dose. In
addition to PK and PD, this study will carefully assess clinical disease course and adverse
events (AEs), including neurologic AEs. Safety evaluations also will include neurologic
assessments, general physical assessments, and AE and serious adverse event (SAE) reporting.
Sequential nasopharyngeal specimens will be obtained for virologic assessments, including
viral cultures, polymerase chain reaction (PCR) for viral ribonucleic acid (RNA)
(quantitative), and analysis of antiviral resistance.