Oseltamivir pharmacokinetics, dosing, and resistance among children aged David W Kimberlin  1 , Edward P Acosta, Mark N Prichard, Pablo J Sánchez, Krow Ampofo, David Lang, Negar Ashouri, John A Vanchiere, Mark J Abzug, Nazha Abughali, Mary T Caserta, Janet A Englund, Sunil K Sood, Michael G Spigarelli, John S Bradley, Judy Lew, Marian G Michaels, Wen Wan, Gretchen Cloud, Penelope Jester, Fred D Lakeman, Richard J Whitley; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group Collaborators, Affiliations Expand Collaborators National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Dusty Giles, Bari Cotton, Sharon Judy, Margaret Cowie, Jeanne Francis, Candice Evans, Nan O'Donnell, Ofelia Vargas Shiraishi, Lisa Latiolais, Valeri Aymami, Ken Dole, Julie Gaultier, Gerry Lofthus, Diane Kinnunen, Kirsten Lacombe, Nancy Stellato, Julie Denlinger, Sara Hingtgen, Christina Mason, Noreen Jeffrey Affiliation 1 Department of Pediatrics, University of Alabama at Birmingham, AL 35233, USA. dkimberlin@peds.uab.edu PMID: 23230059 PMCID: PMC3563309 DOI: 10.1093/infdis/jis765 Free PMC article Item in Clipboard

Abstract

Background: Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown.

Methods: The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure.

Results: From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment.

Conclusions: The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.

Trial registration: ClinicalTrials.gov NCT00391768.

Figures

Figure 1.

Screening, enrollment, and follow-up during the course of the study.

Figure 2.

Oseltamivir carboxylate geometric mean 12-hour area under the concentration curve (AUC12), by age and dosage cohort, with target and range.

Figure 3.

Decline in nasopharyngeal influenza virus load over time, by age and dosage cohort.