title: Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response.
abstract: 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.
  
  
  
  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.
  
  
  
  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 Cmax values with adults.
  
  
  
  The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposure-response 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.
authors.affiliation: *US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD †Former Employee of AstraZeneca R&D Mölndal, Mölndal, Sweden ‡Novo Nordisc, Aalborg Øst, Denmark §Department of Biopharmaceutical Sciences, Uppsala University, Uppsala, Sweden ||Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, The Netherlands.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Earp
authors.forename: Nitin
authors.initials: N
authors.lastname: Mehrotra
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Peters
authors.forename: Robert P
authors.initials: RP
authors.lastname: Fiorentino
authors.forename: Donna
authors.initials: D
authors.lastname: Griebel
authors.forename: Sue C
authors.initials: SC
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: Mulberg
authors.forename: Kerstin
authors.initials: K
authors.lastname: Röhss
authors.forename: Marie
authors.initials: M
authors.lastname: Sandström
authors.forename: Amy
authors.initials: A
authors.lastname: Taylor
authors.forename: Christoffer W
authors.initials: CW
authors.lastname: Tornøe
authors.forename: Erica L
authors.initials: EL
authors.lastname: Wynn
authors.forename: Jan-Stefan
authors.initials: JS
authors.lastname: Van der Walt
authors.forename: Christine
authors.initials: C
authors.lastname: Garnett
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval / Q000379:methods*; D054796:Drug Dosage Calculations; D064098:Esomeprazole / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult
chemical_list: D054328:Proton Pump Inhibitors; D064098:Esomeprazole