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

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Abstract

Background

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

Aim

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

Methods

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.

Results

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.

Conclusions

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.

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Notes

  1. Preterm infants were defined as infants who were born before 37 completed weeks of gestation. Neonates were defined as term or postterm infants in the first 28 days since birth. Term infants were defined as those born after 37–42 weeks of gestation, and postterm infants were defined as those born after 42 weeks of gestation. Gestational age was the estimated number of weeks between the first day of the mother’s last menstrual period and the day of delivery. Postnatal age was the age since birth in weeks. Corrected age in study 1, also referred to in the literature as postmenstrual age, was the sum of gestational age and the age since birth in weeks.

References

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  4. Callahan CW. Increased gastroesophageal reflux in infants: can history provide an explanation? Acta Paediatr. 1998;87:1219–1223.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  6. Baker SS, Roach CM, Leonard MS, Baker RD. Infantile gastroesophageal reflux in a hospital setting. BMC Pediatr. 2008;8:11.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. Di Lorenzo C, Winter HS. Introduction. J Pediatr Gastroenterol Nutr. 2003;37(suppl 1):S1.

    Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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).

  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.

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  24. American Gastroenterological Association. American Gastroenterological Association medical position statement: guidelines on the use of esophageal pH recording. Gastroenterology. 1996;110:1981–1996.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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. 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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

These studies were sponsored by Wyeth Research, which was acquired by Pfizer Inc. in October 2009. The authors thank Tuli Ahmed for providing professional medical writing assistance funded by Wyeth Research. The following investigators participated in the PD portion of study 1: Tracie L. Miller, University of Miami, Miller School of Medicine, Miami, FL, USA; Mark J. Polak, West Virginia University School of Medicine, Department of Pediatrics, Morgantown, WV, USA; Dan L. Stewart, Kosair Charities Pediatric Clinical Research Unit and Pediatric Pharmacology Research Unit (NICHD 1 U10 HD 0495934-04), University of Louisville, Louisville, KY, USA; Manoj C. Shah, Loma Linda University, Department of Pediatrics, Loma Linda, CA, USA; Elmer David, University of Medicine & Dentistry of NJ, New Jersey Medical School, Newark, NJ, USA; Wanda Furmaga-Jablonska, Department of Neonates’ and Infants’ Pathology, Children’s University Hospital, Medical University of Lublin, Lublin, Poland; Piotr Korbal, Oddzial Noworodkow i Wczesniakow z Intensywna Terapia Noworodka, SP ZOZ Wojewodzki Szpital im. Dr J. Biziela, Bydgoszcz, Poland; Christophe Dupont, Hôpital Saint Vincent de Paul, Service de Médecine Néonatale, Paris, France; Bart van Overmeire, University Hospital Antwerp, Department of Neonatology, Edegem, Belgium; and Salvatore Cucchiara, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy. The following investigators participated in the PD portion of study 2: Janice E. Sullivan, Kosair Charities Pediatric Clinical Research Unit and Pediatric Pharmacology Research Unit (NICHD 1 U10 HD 0495934-04), University of Louisville, Louisville, KY, USA; Steven Lobritto, Columbia University Medical Center, Division of Pediatric Gastroenterology, Hepatology & Nutrition, New York, NY, USA; Jaroslaw Kierkus, Department of Gastroenterology, Hepatology and Immunology, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, Warsaw, Poland; Wanda Furmaga-Jablonska, Department of Neonates’ and Infants’ Pathology, Children’s University Hospital, Medical University of Lublin, Lublin, Poland; Christophe Dupont, Hôpital Saint Vincent de Paul, Service de Médecine Néonatale, Paris, France; Burkhard Rodeck, Marienhospital, Klinik fuer Kinderheilkunde und Jugendmedizin, Osnabrueck, Germany; Alberto Ravelli, Gastrointestinal Pathophysiology and Endoscopy, University Department of Pediatrics, Children’s Hospital, Spedali Civili, Brescia, Italy; Annamaria Staiano, Dipartimento di Pediatria, Università di Napoli, “Federico II,” Napoli, Italy; Peter Lewindon, Department of Gastroenterology, Royal Children’s Hospital, Herston, Queensland, Australia; and Etienne Sokal, Université Catholique de Louvain, Cliniques St. Luc, Brussels, Belgium.

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Correspondence to Gail M. Comer.

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Kierkus, J., Furmaga-Jablonska, W., Sullivan, J.E. et al. Pharmacodynamics and Safety of Pantoprazole in Neonates, Preterm Infants, and Infants Aged 1 Through 11 Months with a Clinical Diagnosis of Gastroesophageal Reflux Disease. Dig Dis Sci 56, 425–434 (2011). https://doi.org/10.1007/s10620-010-1321-3

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