Safety,Virology and Pharmacokinetics of Oseltamivir in Infants with Laboratory-Confirmed Influenza: A Phase I/II,Prospective,Open-Label,Multicentre Clinical Trial
Free accessResearch articleFirst published online November, 2015
Safety,Virology and Pharmacokinetics of Oseltamivir in Infants with Laboratory-Confirmed Influenza: A Phase I/II,Prospective,Open-Label,Multicentre Clinical Trial
The influenza antiviral oseltamivir is not licensed for infants aged <1 year in most countries outside the United States. More information is needed on oseltamivir safety at different dosing levels in this vulnerable age group.
Methods
In this prospective, observational, non-randomized study, infants aged <1 year with laboratory-confirmed influenza were treated with oral oseltamivir for 5 days. Cohorts 1, 2 and 3 (aged 91–364, 31–90 and 0–30 days, respectively), received twice-daily dosages of 3, 2.5 and 2 mg/kg, respectively. Assessments included pharmacokinetics, on-treatment adverse events, resistance testing and viral shedding.
Results
A total of 65 patients were enrolled: 40, 20 and 5 in cohorts 1, 2 and 3, respectively. Systemic exposure to oseltamivir carboxylate (active metabolite) reached therapeutic levels in all patients, with an adequate safety margin. On-treatment adverse events (n=48) were reported by 32 patients (49%). At least one adverse event was reported by 43%, 65% and 40% of infants in cohorts 1, 2 and 3, respectively; most frequently vomiting and diarrhoea. Eight serious adverse events were reported, all of which were considered unrelated to treatment by the investigator. No deaths occurred and no patient had treatment withdrawn. Oseltamivir resistance mutations were detected in eight patients.
Conclusions
Oseltamivir dosages of 2–3 mg/kg were well tolerated in infants aged <1 year and achieved therapeutic exposure levels. The current study supports the adoption of a universal dosing recommendation for infants. Clinicaltrials.gov unique identifier NCT00988325.
References
1.
AmpofoK., GestelandP.H., BenderJ.Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection.Pediatrics2006; 118: 2409–2417.
2.
BhatN., WrightJ.G., BroderK.R.Influenza-associated deaths among children in the United States, 2003-2004.N Engl J Med2005; 353: 2559–2567.
3.
LoughlinJ., PouliosN., NapalkovP., WegmüllerY., MontoA.S.A study of influenza and influenza-related complications among children in a large US health insurance plan database.Pharmacoeconomics2003; 21: 273–283.
4.
SmithJ.R., RaynerC.R., DonnerB., WollenhauptM., KlumppK., DutkowskiR.Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience.Adv Ther2011; 28: 927–959.
OoC., BarrettJ., HillG.Pharmacokinetics and dosage recommendations for an oseltamivir oral suspension for the treatment of influenza in children.Paediatr Drugs2001; 3: 229–236.
8.
AcostaE.P., KimberlinD.W.Determination of appropriate dosing of influenza drugs in pediatric patients.Clin Pharmacol Ther2010; 88: 704–707.
9.
ShiD., YangD., PrinssenE.P., DaviesB.E., YanB.Surge in expression of carboxylesterase 1 during the post-neonatal stage enables a rapid gain of the capacity to activate the anti-influenza prodrug oseltamivir.J Infect Dis2011; 203: 937–942.
10.
Strolin BenedettiM., WhomsleyR., BaltesE.L.Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations.Expert Opin Drug Metab Toxicol2005; 1: 447–471.
KamalM.A., AcostaE.P., KimberlinD.W.The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach.Clin Pharmacol Ther2014; 96: 380–389.
15.
KimberlinD.W., AcostaE.P., PrichardM.N.Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza.J Infect Dis2013; 207: 709–720.
16.
NicholsonK.G., AokiF.Y., OsterhausA.D.Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial.Lancet2000; 355: 1845–1850.
17.
TreanorJ.J., HaydenF.G., VroomanP.S.Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group.JAMA2000; 283: 1016–1024.
18.
FioreA.E., FryA., ShayD.Antiviral agents for the treatment and chemoprophylaxis of influenza – recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep2011; 60: 1–24.
19.
RathB., von KleistM., TiefF.Virus load kinetics and resistance development during oseltamivir treatment in infants and children infected with Influenza A(H1N1) 2009 and Influenza B viruses.Pediatr Infect Dis J2012; 31: 899–905.
20.
WhitleyR.J., HaydenF.G., ReisingerK.S.Oral oseltamivir treatment of influenza in children.Pediatr Infect Dis J2001; 20: 127–133.
21.
SiedlerK., SkopnikH.Oseltamivir for treatment of influenza in infants less than one year: a retrospective analysis.Pediatr Infect Dis J2010; 29: 495–498.
22.
DonnerB., Bader-WederS., SchwarzR., PengM.M., SmithJ.R., NiranjanV.Safety profile of oseltamivir during the 2009 influenza pandemic.Pharmacoepidemiol Drug Saf2011; 20: 532–543.
23.
RathB.A., BlumentalsW.A., MillerM.K., StarzykK., TetiurkaB., WollenhauptM.A prospective observational study of oseltamivir safety and tolerability in infants and young children ≤24 months.Pharmacoepidemiol Drug Saf2015; 24: 286–296.
24.
HeinonenS., SilvennoinenH., LehtinenP.Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial.Clin Infect Dis2010; 51: 887–894.
25.
EspositoS., DalenoC., BaldantiF.Viral shedding in children infected by pandemic A/H1N1/2009 influenza virus.Virol J2011; 8: 349.
26.
LiC.C., WangL., EngH.L.Correlation of pandemic (H1N1) 2009 viral load with disease severity and prolonged viral shedding in children.Emerg Infect Dis2010; 16: 1265–1272.
27.
WhitleyR.J., BoucherC.A., LinaB.Global assessment of resistance to neuraminidase inhibitors, 2008-2011: the Influenza Resistance Information Study (IRIS).Clin Infect Dis2013; 56: 1197–1205.
