Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza

David W. Kimberlin; 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; 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

doi:10.1093/infdis/jis765

Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza

David W. Kimberlin, 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 JesterFred D. Lakeman, Richard J. Whitley, 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

Pediatrics

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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.Clinical Trials Registration. NCT00391768.

Original language	English (US)
Pages (from-to)	709-720
Number of pages	12
Journal	Journal of Infectious Diseases
Volume	207
Issue number	5
DOIs	https://doi.org/10.1093/infdis/jis765
State	Published - Mar 1 2013

Keywords

Oseltamivir
Tamiflu
antiviral resistance
antiviral treatment
influenza

ASJC Scopus subject areas

Immunology and Allergy
Infectious Diseases

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10.1093/infdis/jis765

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Kimberlin, D. W., Acosta, E. P., Prichard, M. N., Sánchez, P. J., Ampofo, K., Lang, D., Ashouri, N., Vanchiere, J. A., Abzug, M. J., Abughali, N., Caserta, M. T., Englund, J. A., Sood, S. K., Spigarelli, M. G., Bradley, J. S., Lew, J., Michaels, M. G., Wan, W., Cloud, G., ... Jeffrey, N. (2013). Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. Journal of Infectious Diseases, 207(5), 709-720. https://doi.org/10.1093/infdis/jis765

Kimberlin, DW, Acosta, EP, Prichard, MN, Sánchez, PJ, Ampofo, K, Lang, D, Ashouri, N, Vanchiere, JA, Abzug, MJ, Abughali, N, Caserta, MT, Englund, JA, Sood, SK, Spigarelli, MG, Bradley, JS, Lew, J, Michaels, MG, Wan, W, Cloud, G, Jester, P, Lakeman, FD, Whitley, RJ, Giles, D, Cotton, B, Judy, S, Cowie, M, Francis, J, Evans, C, O'donnell, N, Shiraishi, OV, Latiolais, L, Aymami, V, Dole, K, Gaultier, J, Lofthus, G, Kinnunen, D, Lacombe, K, Stellato, N, Denlinger, J, Hingtgen, S, Mason, C & Jeffrey, N 2013, 'Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza', Journal of Infectious Diseases, vol. 207, no. 5, pp. 709-720. https://doi.org/10.1093/infdis/jis765

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title = "Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza",

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.Clinical Trials Registration. NCT00391768.",

keywords = "Oseltamivir, Tamiflu, antiviral resistance, antiviral treatment, influenza",

author = "Kimberlin, {David W.} and Acosta, {Edward P.} and Prichard, {Mark N.} and S{\'a}nchez, {Pablo J.} and Krow Ampofo and David Lang and Negar Ashouri and Vanchiere, {John A.} and Abzug, {Mark J.} and Nazha Abughali and Caserta, {Mary T.} and Englund, {Janet A.} and Sood, {Sunil K.} and Spigarelli, {Michael G.} and Bradley, {John S.} and Judy Lew and Michaels, {Marian G.} and Wen Wan and Gretchen Cloud and Penelope Jester and Lakeman, {Fred D.} and Whitley, {Richard J.} and Dusty Giles and Bari Cotton and Sharon Judy and Margaret Cowie and Jeanne Francis and Candice Evans and Nan O'donnell and Shiraishi, {Ofelia Vargas} and Lisa Latiolais and Valeri Aymami and Ken Dole and Julie Gaultier and Gerry Lofthus and Diane Kinnunen and Kirsten Lacombe and Nancy Stellato and Julie Denlinger and Sara Hingtgen and Christina Mason and Noreen Jeffrey",

note = "Funding Information: Financial support. This work was supported by the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (contracts N01-AI-30025, N01-AI -65306, N01-AI -15113, and N01-AI-62554). Assays of oseltamivir and oseltamivir carboxylate concentrations in plasma were provided by F. Hoffman–La Roche.",

year = "2013",

month = mar,

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doi = "10.1093/infdis/jis765",

language = "English (US)",

volume = "207",

pages = "709--720",

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T1 - Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza

AU - Kimberlin, David W.

AU - Acosta, Edward P.

AU - Prichard, Mark N.

AU - Sánchez, Pablo J.

AU - Ampofo, Krow

AU - Lang, David

AU - Ashouri, Negar

AU - Vanchiere, John A.

AU - Abzug, Mark J.

AU - Abughali, Nazha

AU - Caserta, Mary T.

AU - Englund, Janet A.

AU - Sood, Sunil K.

AU - Spigarelli, Michael G.

AU - Bradley, John S.

AU - Lew, Judy

AU - Michaels, Marian G.

AU - Wan, Wen

AU - Cloud, Gretchen

AU - Jester, Penelope

AU - Lakeman, Fred D.

AU - Whitley, Richard J.

AU - Giles, Dusty

AU - Cotton, Bari

AU - Judy, Sharon

AU - Cowie, Margaret

AU - Francis, Jeanne

AU - Evans, Candice

AU - O'donnell, Nan

AU - Shiraishi, Ofelia Vargas

AU - Latiolais, Lisa

AU - Aymami, Valeri

AU - Dole, Ken

AU - Gaultier, Julie

AU - Lofthus, Gerry

AU - Kinnunen, Diane

AU - Lacombe, Kirsten

AU - Stellato, Nancy

AU - Denlinger, Julie

AU - Hingtgen, Sara

AU - Mason, Christina

AU - Jeffrey, Noreen

N1 - Funding Information: Financial support. This work was supported by the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (contracts N01-AI-30025, N01-AI -65306, N01-AI -15113, and N01-AI-62554). Assays of oseltamivir and oseltamivir carboxylate concentrations in plasma were provided by F. Hoffman–La Roche.

PY - 2013/3/1

Y1 - 2013/3/1

N2 - 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.Clinical Trials Registration. NCT00391768.

AB - 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.Clinical Trials Registration. NCT00391768.

KW - Oseltamivir

KW - Tamiflu

KW - antiviral resistance

KW - antiviral treatment

KW - influenza

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Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza

Abstract

Keywords

ASJC Scopus subject areas

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