Earp CJ et al. – This study described exposure–response and exposure–matching analysis for identifying the approvable pediatric doses of esomeprazole in children with gastroesophageal reflux disease (GERD). The authors concluded that the exposure–matching analysis facilitated the approval of esomeprazole regimen, which was not evaluated directly in clinical trials. On the other hand, exposure–response for intragastric pH–enabled approval for the treatment of GERD in children in whom evaluation of mucosal healing assessed by endoscopy (adult primary endpoint) was not feasible.

Methods

• Comparison of intragastric pH biomarker were performed between children and adults.
• Population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data was used for the selection of pediatric doses for matching the exposures in adults.
• A population PK model was developed using the existing PK data pertaining to intravenous (IV) or oral esomeprazole from children (birth and 17 years) and adults (20 and 48 years) to simulate steady–state esomeprazole exposures for children at different doses to match the exposures in adults.

Results

• Children and adults revealed similar exposure–response relationships of intragastric pH measures.
• The dosing regimen identified for children using PK simulations resulted in comparable steady–state area under the curve to that observed following 20 mg in adults.
Increasing the infusion duration of IV esomeprazole to 10 to 30 minutes in children resulted in achieving matching maximum (or peak) serum concentration (Cmax) values with adults.