Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD)
- 741 Downloads
The pharmacokinetic profile of pantoprazole granules was assessed in neonates and preterm infants with gastroesophageal reflux disease (GERD) in a multicenter, randomized, open-label trial.
Patients were randomly assigned to either the pantoprazole 1.25 mg (approx. 0.6 mg/kg) or 2.5 mg (approx. 1.2-mg/kg) group and treated for ≥5 consecutive days. Blood was sampled either at 0, 2, 8, and 18 h postdose or at 0, 1, 4, and 12 h postdose on day 1 and at 3 and 6 h postdose after ≥5 consecutive doses. Cytochrome P450 2C19 (CYP2C19) and CYP3A4 genotypes were determined. Safety was monitored. Population pharmacokinetics (popPK) analyses were conducted using nonlinear mixed-effects modeling.
The popPK modeling of the pantoprazole 1.25 mg and 2.5 mg groups obtained mean (±standard deviation) estimates for the area under the plasma concentration versus time curve (AUC) of 3.54 (±2.82) and 7.27 (±5.30) µg h/mL, respectively, and mean estimates for half-life of 3.1 (±1.5) and 2.7 (±1.1) h, respectively. Pantoprazole did not accumulate following multiple-dose administration. The two patients with the CYP2C19 poor metabolizer genotype had a substantially higher AUC than extensive metabolizers. No safety-related discontinuations occurred.
In preterm infants and neonates, pantoprazole granules were generally well tolerated, mean exposures with pantoprazole 2.5 mg were slightly higher than that in adults who received 40 mg. While the half-life was longer, accumulation did not occur.
KeywordsGastroesophageal reflux Infant, premature Infant, newborn Pantoprazole Pharmacokinetics
This study was sponsored by Wyeth Research, which was acquired by Pfizer Inc. in October 2009. Medical writing support was provided by Tuli Ahmed, medical writer, of On Assignment, and funded by Wyeth.
The following investigators participated in the PK portion of this study: Venkataraman Balaraman, Kapiolani Medical Center for Women & Children, Honolulu, HI; Georges Caouette, Centre Hospitalier Universitaire de Québec–Centre Hospitalier Universite Laval, Sainte-Foy, Québec, Canada; Elmer David, University of Medicine & Dentistry of NJ–New Jersey Medical School, Newark, NJ; William D. Engle, University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Marilyn Escobedo, University of Oklahoma, College of Medicine, Oklahoma City, OK; Neil Finer, UCSD, San Diego, CA; Wanda Furmaga-Jablonska, Children’s University Hospital, Medical University of Lublin, Lublin, Poland; De-Ann M. Pillers, Oregon Health and Science University, Portland, OR; Mark Polak, West Virginia University School of Medicine, Morgantown, WV; Henry Rozycki, Virginia Commonwealth University, Richmond, VA; Matthew Sell, St Alphonsus Hospital, Boise, ID, Boise, ID; Harohali Shashidhar, University of Kentucky Medical Center, Lexington, KY; Robin Steinhorn, Children's Memorial Hospital and Northwestern University, Chicago, IL; Mitchell Stern, Plantation General Hospital, Plantation, FL; Dan L. Stewart, University of Louisville, Louisville, KY; Sandra E. Sullivan, University of Florida & Shands Hospital, Gainesville, FL; and Sajani Tipnis, Children’s Hospital of Wisconsin, Milwaukee, WI.
Financial disclosure / conflict of interest
Drs. Ward, Sullivan, and Stewart were investigators in the study, and they or their institutions were compensated by Wyeth Research for their participation in the study. Dr. Ward was a consultant for Wyeth in the design of this study. Drs. Ward and Sullivan do not hold stock in the company. Dr. Ward is supported in part by NIH U10 HD045986. Dr. Sullivan received research and/or service grant support from Prolacta Bioscience, W.K. Kellogg Foundation, and the Thomas H. Maren Foundation for unrelated work in the past 12 months. Drs. Tammara, Rath, Meng, Maguire, and Comer were Wyeth employees at the time of the study and may have held stock in Wyeth. Wyeth was acquired by Pfizer in October 2009.
- 1.Wyeth (2008) PROTONIX (pantoprazole sodium) delayed-release tablets and PROTONIX (pantoprazole sodium) for delayed-release oral suspension (prescribing information). Wyeth, PhiladelphiaGoogle Scholar
- 2.Tammara B, Orczyk G, Nightingale C, Hoy M, Meng X (2004) Bioavailability of the new pantoprazole spheroid formulation to the currently marketed tablet formulation in healthy adult subjects [AAPS abstract 275). AAPS J 6[Suppl 1]. Available at: www.aapsj.org/abstracts/AM_2004/AAPS2004-000275.PDF. Accessed on October 12, 2009
- 3.Hogan D, Pratha V, Riff D et al (2007) Oral pantoprazole in the form of granules or tablets are pharmacodynamically equivalent in suppressing acid output in patients with gastro-oesophageal reflux disease and a history of erosive oesophagitis. Aliment Pharmacol Ther 26:249–256CrossRefPubMedGoogle Scholar
- 4.Tammara B, Ward R, Kearns G et al (2008) Pharmacokinetics of single and multiple doses of pantoprazole in adolescents with GERD (ACG abstract 1347). Am J Gastroenterol 103[Suppl 1]:S528Google Scholar
- 5.Tammara B, Sullivan J, Springer M et al (2008) 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 (abstract 1346). Am J Gastroenterol 103[Suppl 1]:S527–S528Google Scholar
- 6.Tammara B, Adcock K, Kearns G et al (2008) Pharmacokinetics of two dose levels of pantoprazole sodium granules and tablets in children aged 1 through 11 years with endoscopically proven GERD (abstract 1348). Am J Gastroenterol 103[Suppl 1]:S528–S529Google Scholar
- 15.Comer GM, Tammara B, Adcock K, et al (2005) Pharmacokinetics of intravenous pantoprazole in children ages 1 to 16 years (abstract 1023). Am J Gastroenterol [Suppl 9 s]:S373Google Scholar
- 17.Omari T, Lundborg P, Sandstrom M et al (2009) Pharmacodynamics and systemic exposure of esomeprazole in preterm infants and term neonates with gastroesophageal reflux disease. J Pediatr 55:222–228Google Scholar
- 19.Kearns G, Ferron GM, James LP et al (2003) Pantoprazole disposition in pediatrics (abstract PII-35). Clin Pharm Ther 73(2):P38Google Scholar