Related Experiment Video
Updated: Mar 11, 2026
Simultaneous Laryngopharyngeal and Conventional Esophageal pH Monitoring
Published on: December 14, 2020
Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response
Justin C Earp1, Nitin Mehrotra, Kristina E Peters
1*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.
Insights
This study used pharmacokinetic modeling to determine appropriate pediatric doses for esomeprazole, enabling FDA approval for treating gastroesophageal reflux disease in children. The findings support matching adult drug exposures in pediatric patients.
Area of Science:
- Pharmacology
- Pediatric Gastroenterology
- Drug Development
Background:
- Gastroesophageal reflux disease (GERD) treatment in children faces challenges due to variability in clinical assessment.
- Extrapolation of adult efficacy data for intravenous (IV) esomeprazole to pediatric patients (1-17 years) was previously accepted.
- Oral esomeprazole formulations have prior approval in pediatric populations.
Purpose of the Study:
- To identify approvable pediatric doses for esomeprazole by conducting exposure-response and exposure-matching analyses.
- To address limitations in Food and Drug Administration (FDA) approval for proton-pump inhibitors in infantile GERD.
- To establish pediatric dosing regimens that align with adult exposures.
Main Methods:
- Compared intragastric pH biomarkers between pediatric and adult populations.
- Utilized population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data (oral and IV) from 167 children and 65 adults.
- Simulated pediatric esomeprazole exposures at various doses to match adult steady-state exposures.
Main Results:
- Demonstrated similar exposure-response relationships for intragastric pH measures in children and adults.
- Identified a pediatric dosing regimen yielding comparable steady-state area under the curve (AUC) to the adult 20 mg dose.
- Achieved matching Cmax values for IV esomeprazole in children by extending infusion duration to 10-30 minutes.
Conclusions:
- Exposure-matching analysis facilitated the approval of an esomeprazole regimen not directly evaluated in clinical trials.
- Exposure-response data for intragastric pH supported approval for treating pediatric GERD, particularly when adult endpoints like mucosal healing were not feasible.
- Established a scientific basis for pediatric esomeprazole dosing through PK modeling and exposure matching.
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 Cmax values with adults.
Conclusions:
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.
Related Concept Videos
01:29Gastroesophageal Reflux Disease II: Clinical Features and Management
Clinical Manifestations
GERD presents itself in a multitude of ways, with symptoms varying from person to person. The hallmark symptoms are...
01:13Acid Suppressive Drugs for Peptic Ulcer Disease: Proton Pump Inhibitors
Gastric acid, a potent cocktail of hydrogen and chloride ions, is produced in specialized parietal cells within the...
01:23Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption
01:24Drugs for Peptic Ulcer Disease: Sucralfate as Mucosal Protective Agents
In this scenario, mucosal protective agents like sucralfate play an essential role. Sucralfate, a complex of sulfated sucrose and aluminum hydroxide, demonstrates its usefulness in acidic conditions,...
01:28Acid Suppressive Drugs for Peptic Ulcer Disease: Histamine H2-Receptor Antagonists
01:26Peptic Ulcer Disease IV: Management
The therapeutic approach involves ensuring adequate rest, implementing drug therapy, promoting smoking cessation, making dietary modifications, and emphasizing long-term follow-up care.
Pharmacological management
The prevailing therapy for peptic ulcers involves a combination of managing the patient's current...