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Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response
US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
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2017 (English)In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 65, no 3, p. 272-277Article in journal (Refereed) Published
Abstract [en]

Objectives: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. Methods: Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults. Results: Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching C-max values with adults. Conclusions: The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposureresponse for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2017. Vol. 65, no 3, p. 272-277
Keywords [en]
biomarker, esomeprazole, exposure-matching, exposure-response, pediatric, pharmacokinetics
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:uu:diva-335638DOI: 10.1097/MPG.0000000000001467ISI: 000408995000014PubMedID: 27875488OAI: oai:DiVA.org:uu-335638DiVA, id: diva2:1165912
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2017-12-14Bibliographically approved

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van der Walt, Jan-Stefan

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