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

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.

Inclusion Criteria:

1. Signed informed consent and HIPAA documents by parent/legal guardian.

2. Hospitalized premature neonates (Post menstrual age (PMA) 28 - < 34 weeks), neonates
(PMA 34 to 44 weeks), and infants (PMA > 44 weeks to 11 months).

3. Clinical indication for acid suppression or a presumptive diagnosis of GERD based on
clinical symptoms and/or objective tests diagnostic of GERD.

4. Body weight of at least 750 grams (based on blood volume required for study
participation).

Exclusion Criteria:

1. Previous adverse reaction to proton pump inhibitor

2. History of gastrointestinal anomalies, eosinophilic esophagitis, unrepaired tracheal
esophageal fistula or liver disease

3. Unstable cardiovascular, renal, hepatic, hematologic or endocrine disease

4. History of acute life-threatening events due to GERD

5. History of hepatitis B or hepatitis C

6. Use of PPI's within 24 hours before study drug is administered

7. Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome

8. Clinically significant laboratory values:

- Aspartate aminotransferase (AST) or alanine aminotransferase (AST) >2 times the
upper limit of normal (ULN) for age

- Total bilirubin > 2 times ULN for age

- Alkaline phosphatase > 2 times ULN for age

10.Use of histamine-2 receptor blockers (eg. Cimetidine, famotidine, ranitidine, or
nizatidine) sucralfate, misoprostol, or prokinetic agents (eg. urecholine, erythromycin,
or metoclopramide) and antacids or bismuth preparations within 24 hours before test
article administration.

11.Any disorder requiring chronic use of warfarin, oxcarbazepine, topiramate,
carbamezapine, rifampin or phenytoin.

12.Currently participating in another investigational drug trial or have participated in a
study within the last 30 days.