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Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD)

  • Clinical Trial
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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Notes

  1. Preterm infants were defined as infants who were born before 37 complete weeks of gestation. Neonates were defined as term or postterm infants in the first 28 days after birth. Term infants were defined as those born after 37 to 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, also referred to as postmenstrual age, was the sum of gestational age and the age since birth in weeks.

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Acknowledgments

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.

Investigators

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.

Author information

Authors and Affiliations

  1. Pediatric Pharmacology Program, Department of Pediatrics, University of Utah, 417 Wakara, Suite 3510, Salt Lake, UT, 84108, USA

    Robert M. Ward

  2. Pfizer Inc., Collegeville, PA, USA

    Brinda Tammara, Natalie Rath, Xu Meng, Mary K. Maguire & Gail M. Comer

  3. Department of Pediatrics, University of Florida & Shands Children’s Hospital, Gainesville, FL, USA

    Sandra E. Sullivan

  4. Kosair Charities Pediatric Clinical Research Unit, University of Louisville, Louisville, KY, USA

    Dan L. Stewart

Authors
  1. Robert M. Ward
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  2. Brinda Tammara
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  3. Sandra E. Sullivan
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  4. Dan L. Stewart
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  5. Natalie Rath
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  6. Xu Meng
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  7. Mary K. Maguire
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  8. Gail M. Comer
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Corresponding author

Correspondence to Robert M. Ward.

Additional information

This trial is registered at http://www.clinicaltrials.gov as no. NCT00362609.

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Ward, R.M., Tammara, B., Sullivan, S.E. et al. Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD). Eur J Clin Pharmacol 66, 555–561 (2010). https://doi.org/10.1007/s00228-010-0811-8

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  • DOI: https://doi.org/10.1007/s00228-010-0811-8

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