Digestive Diseases and Sciences

, Volume 56, Issue 2, pp 425–434 | Cite as

Pharmacodynamics and Safety of Pantoprazole in Neonates, Preterm Infants, and Infants Aged 1 Through 11 Months with a Clinical Diagnosis of Gastroesophageal Reflux Disease

  • Jaroslaw Kierkus
  • Wanda Furmaga-Jablonska
  • Janice E. Sullivan
  • Elmer S. David
  • Dan L. Stewart
  • Natalie Rath
  • Caifeng Fu
  • Wenjin Wang
  • Mary K. Maguire
  • Gail M. Comer
Original Article



Limited data on proton pump inhibitors in infants led regulatory agencies to request sponsors to conduct pediatric studies.


To determine the pharmacodynamic response to pantoprazole in infants with GERD to aid the dose selection for an efficacy study.


In two open-label studies, neonates and preterm infants (study 1, ~1.2 mg/kg [high dose]) and infants 1 through 11 months (study 2, ~0.6 [low dose] or ~1.2 mg/kg [high dose]) received once-daily pantoprazole. Twenty-four-hour dual-electrode pH-metry parameters were compared between predose and steady state (≥5 days) (two-sided paired t test). Treatment was administered for ≤6 weeks.


In studies 1 and 2, 21 and 24 patients, respectively, were enrolled for pharmacodynamic evaluation. The high dose provided similar responses in the two studies and improved these parameters significantly: mean gastric pH and percent time gastric pH > 4 increased (p < 0.05 both studies), normalized area under the curve (AUC) of gastric H+ activity decreased (p < 0.05 study 2), and normalized AUC of esophageal H+ activity decreased (p < 0.05 both studies). The AUC of esophageal pH < 4 decreased. Normalized AUC of esophageal H+ activity decreased (p < 0.05 both studies), indicating refluxate pH increased, although this was not reflected in any change in mean esophageal pH or reflux index. The normalized AUC of esophageal H+ activity was a more sensitive measure of changes in esophageal pH.


In neonates, preterm infants, and infants aged 1 through 11 months, pantoprazole (high dose) improved pH-metry parameters after ≥5 consecutive daily doses, and was generally well tolerated for ≤6 weeks.


Premature infant Newborn infant Infant Gastric acidity determination Gastroesophageal reflux Pharmacodynamics 


  1. 1.
    Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2009;49:498–547.CrossRefPubMedGoogle Scholar
  2. 2.
    Sherman PM, Hassall E, Fagundes-Neto U, et al. A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population. Am J Gastroenterol. 2009;104:1278–1295.CrossRefPubMedGoogle Scholar
  3. 3.
    Barron JJ, Tan H, Spalding J, Bakst AW, Singer J. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr. 2007;45:421–427.CrossRefPubMedGoogle Scholar
  4. 4.
    Callahan CW. Increased gastroesophageal reflux in infants: can history provide an explanation? Acta Paediatr. 1998;87:1219–1223.CrossRefPubMedGoogle Scholar
  5. 5.
    Dhillon AS, Ewer AK. Diagnosis and management of gastro-oesophageal reflux in preterm infants in neonatal intensive care units. Acta Paediatr. 2004;93:88–93.CrossRefPubMedGoogle Scholar
  6. 6.
    Baker SS, Roach CM, Leonard MS, Baker RD. Infantile gastroesophageal reflux in a hospital setting. BMC Pediatr. 2008;8:11.CrossRefPubMedGoogle Scholar
  7. 7.
    Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 2001;32(suppl 2):S1–S31.CrossRefPubMedGoogle Scholar
  8. 8.
    Barney CK, Baer VL, Scoffield SH, Lambert DK, Cook M, Christensen RD. Lansoprazole, ranitidine, and metoclopramide: comparison of practice patterns at 4 level III NICUs within one healthcare system. Adv Neonat Care. 2009;9:129–131.Google Scholar
  9. 9.
    Di Lorenzo C, Winter HS. Introduction. J Pediatr Gastroenterol Nutr. 2003;37(suppl 1):S1.Google Scholar
  10. 10.
    Rudolph CD. Are proton pump inhibitors indicated for the treatment of gastroesophageal reflux in infants and children? J Pediatr Gastroenterol Nutr. 2003;37:S60–S64.CrossRefPubMedGoogle Scholar
  11. 11.
    Colletti R, Di Lorenzo C. Overview of pediatric gastroesophageal reflux disease and proton pump inhibitor therapy. J Pediatr Gastroenterol Nutr. 2003;37(suppl 1):S7–S11.PubMedGoogle Scholar
  12. 12.
    Diaz DM, Winter HS, Colletti RB, et al. Knowledge, attitudes and practice styles of North American pediatricians regarding gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2007;45:56–64.CrossRefPubMedGoogle Scholar
  13. 13.
    Gallo-Torres H. Briefing Document for June 11, 2002 Advisory Committee meeting on the proton-pump inhibitor (PPI) template. Justification for studies in pediatric patients. Available at: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3870B1_02_Briefing%20document.pdf . 2002. Accessed January 25, 2010.
  14. 14.
    Omari T, Lundborg P, Sandstrom M, et al. Pharmacodynamics and systemic exposure of esomeprazole in preterm infants and term neonates with gastroesophageal reflux disease. J Pediatr. 2009;155:222–228.CrossRefPubMedGoogle Scholar
  15. 15.
    Springer M, Atkinson S, North J, Raanan M. Safety and pharmacodynamics of lansoprazole in patients with gastroesophageal reflux disease aged <1 year. Pediatr Drugs. 2008;10:255–263.CrossRefGoogle Scholar
  16. 16.
    Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pediatr Gastroenterol Nutr. 2007;44:41–44.CrossRefPubMedGoogle Scholar
  17. 17.
    Omari T, Davidson G, Bondarov P, Naucler E, Nilsson C, Lundborg P. Pharmacokinetics and acid-suppressive effects of esomeprazole in infants 1–24 months old with symptoms of gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2007;45:530–537.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang W, Kukulka M, Witt G, Sutkowski-Markmann D, North J, Atkinson S. Age-dependent pharmacokinetics of lansoprazole in neonates and infants. Pediatr Drugs. 2008;10:265–274.CrossRefGoogle Scholar
  19. 19.
    Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154:514.e4–520.e4.Google Scholar
  20. 20.
    Winter H, Kum-Nji P, Mahomedy S, et al. Efficacy and safety of pantoprazole delayed-release granules for oral suspension in a placebo-controlled treatment-withdrawal study in infants 1 through 11 months with symptomatic gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. (in press).Google Scholar
  21. 21.
    Maguire MK, Sullivan SE, Stewart DL, et al. Pharmacokinetics of Single and Multiple Doses of Pantoprazole Delayed-Release Granules for Oral Suspension in Neonates and Preterm Infants with a Clinical Diagnosis of Gastroesophageal Reflux Disease (GERD). Poster presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting; December 7–11, 2008, Orlando, FL.Google Scholar
  22. 22.
    Tammara B, Sullivan J, Springer M, et al. Pharmacokinetics of two dose levels of pantoprazole sodium delayed-release granules for oral suspension in infants aged 1 through 11 months with a presumed diagnosis of GERD. Am J Gastroenterol. 2008;103(suppl 1):S527–S528. (Abstract #1346).Google Scholar
  23. 23.
    Omari TI, Benninga MA, Haslam RR, Barnett CP, Davidson GP, Dent J. Lower esophageal sphincter position in premature infants cannot be correctly estimated with current formulas. J Pediatr. 1999;135:522–525.CrossRefPubMedGoogle Scholar
  24. 24.
    American Gastroenterological Association. American Gastroenterological Association medical position statement: guidelines on the use of esophageal pH recording. Gastroenterology. 1996;110:1981–1996.CrossRefGoogle Scholar
  25. 25.
    Salvatore S, Hauser B, Vandemaele K, Novario R, Vandenplas Y. Gastroesophageal reflux disease in infants: how much is predictable with questionnaires, pH-metry, endoscopy and histology? J Pediatr Gastroenterol Nutr. 2005;40:210–215.CrossRefPubMedGoogle Scholar
  26. 26.
    Tolia V, Wuerth A, Thomas R. Diagnostic interpretation of extended pH monitoring: is there a single best method? Dig Dis Sci. 2005;50:94–99.CrossRefPubMedGoogle Scholar
  27. 27.
    Di Fiore JM, Arko M, Churbock K, Hibbs AM, Martin RJ. Technical limitations in detection of gastroesophageal reflux in neonates. J Pediatr Gastroenterol Nutr. 2009;49:177–182.CrossRefPubMedGoogle Scholar
  28. 28.
    Moore D, Tao BSK, Lines D, Hirte C, Heddle M, Davidson G. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr. 2003;143:219–223.CrossRefPubMedGoogle Scholar
  29. 29.
    Winter H, Gunasekaran T, Tolia V, Gottrand F, Barker P, Illueca M. Esomeprazole for the treatment of gastroesophageal reflux disease (GERD) in infants. Gastroenterology. 2009;136(5, suppl 1):A-504 Abstract T1123.Google Scholar
  30. 30.
    Comer G, Baker R, Tsou V, et al. Randomized, double-blind clinical outcomes, safety, and tolerability study of pantoprazole delayed-release granules in children aged 1 to 5 years with endoscopically proven symptomatic gastroesophageal reflux disease (GERD). Gastroenterology. 2009;136(5, suppl 1):A-444 Abstract M1909.Google Scholar
  31. 31.
    Bishop J, Furman M, Thomson M. Omeprazole for gastroesophageal reflux disease in the first 2 years of life: a dose-finding study with dual-channel pH monitoring. J Pediatr Gastroenterol Nutr. 2007;45:50–55.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jaroslaw Kierkus
    • 1
  • Wanda Furmaga-Jablonska
    • 2
  • Janice E. Sullivan
    • 3
  • Elmer S. David
    • 4
  • Dan L. Stewart
    • 3
  • Natalie Rath
    • 5
  • Caifeng Fu
    • 5
  • Wenjin Wang
    • 5
  • Mary K. Maguire
    • 5
  • Gail M. Comer
    • 5
  1. 1.Department of Gastroenterology, Hepatology and ImmunologyThe Children’s Memorial Health InstituteWarsawPoland
  2. 2.Department of Neonates’ and Infants’ Pathology, Children’s University HospitalMedical University of LublinLublinPoland
  3. 3.Department of Pediatrics, Kosair Charities Pediatric Clinical Research Unit/Pediatric Pharmacology Research Unit (NICHD funded through grant U10 HD045934-05)University of LouisvilleLouisvilleUSA
  4. 4.UMDNJ-New Jersey Medical SchoolNewarkUSA
  5. 5.Pfizer Inc.CollegevilleUSA

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