Intravenous (IV) Pantoprazole for Gastroesophageal Reflux Disease (GERD) in Neonates and Infants

Overview

The purpose of this study is to determine how the body uses and eliminates pantoprazole, a drug used to treat GERD. This is a pharmacokinetic (PK) study. PK is a measure of how much drug is in the blood and how long it takes to leave the body. It is hypothesized that younger infants will need a lower dose than older children to achieve the same PK measurement. The results of this study will be used to determine the best dose of the drug to use in each age group. Pantoprazole is a drug used to decrease acid production. The use of pantoprazole has not been approved for use in children. Pantoprazole is approved for use of acid-related and stomach disorders in adults.

Gastroesophageal reflux, regurgitation of gastric contents into the esophagus, and gastroesophageal reflux disease, displaying symptoms and complications from regurgitation, are both very common in infants. Daily reflux is present in up to 50% of infants younger than 3 months and in more than 66% at 4 months of age. GERD is primarily attributed to lower esophageal sphincter relaxation. Between 5-9% of infants less than one year of age have GERD and require acid suppression. Complications associated with GERD include failure to thrive, apnea, wheezing, recurrent aspiration, poor feeding, refusal to feed, irritability, and in more severe cases, acute life-threatening events. Pantoprazole is a proton pump inhibitor that suppresses the final step in gastric acid production through binding to the H+-K+-ATPase enzyme system at the surface of parietal cells in gastric epithelium. This causes a reduction in acid production regardless of the stimulus presented. Pantoprazole is used as therapy in GERD, erosive esophagitis, gastritis, gastric ulcerations, duodenal ulcerations and prophylaxis of stress gastritis in hospitalized patients. Pantoprazole is metabolized mainly by hepatic cytochrome P-450 CYP2C19 and is hypothesized to be metabolized at a higher rate in children as compared to adults. However, the metabolism of proton pump inhibitors is slower in infants \< 10 weeks of age. Clinical studies are ongoing for the use of oral pantoprazole in infants and children. Acid suppression is frequently required in hospitalized infants to treat GERD. In children who are critically ill, oral administration of acid suppressive agents is relatively contraindicated therefore an intravenous alternative such as intravenous pantoprazole is imperative. Intravenous pantoprazole has been well tolerated in pharmacokinetic studies in children ages 1 to 16 years. No systematic studies have been done to determine the pharmacokinetics of intravenous pantoprazole in infants less than 1 year of age therefore this study will meet an identified unmet need and address a knowledge deficit in this population. The aim of this study is to determine the pharmacokinetics of pantoprazole sodium for injection and evaluate the safety and tolerability of single and multiple intravenous doses in preterm neonates and infants 0-11 months of age using population pharmacokinetics. In addition, the genotyping for CYP2C19 and CYP3A4 polymorphisms will be performed.