Randomized, Open-Label, Multicentre Pharmacokinetic Studies of Two Dose Levels of Pantoprazole Granules in Infants and Children Aged 1 Month through <6 Years with Gastro-Oesophageal Reflux Disease
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Background and Objective: The primary objective of this study was to characterize the pharmacokinetic profile of pantoprazole delayed-release granules in infants and children aged 1 month to <6 years with gastro-oesophageal reflux disease (GORD). The studies described in this manuscript were conducted to fulfil the requirements of the paediatric written request for pantoprazole by the US FDA.
Methods: Two randomized, open-label, multicentre studies were conducted in infants aged 1 month to <12 months (study 1) and children aged 1 year through <6 years (study 2) with GORD. Patients were randomly assigned to either the low-dose pantoprazole group (0.6mg/kg equivalent) or the high-dose pantoprazole group (1.2mg/kg equivalent) in a 1:1 fashion. Pantoprazole granules were administered approximately 30 minutes before breakfast for at least five consecutive doses. Blood samples were obtained at prespecified intervals. Plasma pantoprazole concentration-time data were analysed by non-compartmental methods. Descriptive statistics were calculated for pharmacokinetic parameters. Patients in study 2 additionally received pantoprazole for 28 days. Safety was monitored throughout.
Results: In study 1, 43 patients were randomized; 42 were included in the single-dose pharmacokinetic evaluation (15 females, 27 males; mean postnatal age 6.3 months). In study 2,17 patients were randomized, and all were included in the single-dose pharmacokinetic evaluation (6 females, 11 males; mean age 3.2 years). In both studies, exposure increased with dose. Mean (standard deviation) maximum (peak) plasma concentration values for the low and high doses were 503 (506) ng/mL and 1318 (1307) ng/mL, respectively, in study 1, and 229 (196) ng/mL and 653 (645) ng/mL, respectively, in study 2. Area under the plasma concentration-time curve values for the low and high doses were 1046 (1043) ngh/mL and 3602 (3269) ng • h/mL, respectively, in study 1, and 293 (146) ng • h/mL and 2448 (2170) ng • h/mL, respectively, in study 2. There was a trend for increasing clearance with increasing age across the ages 1 month through <6 years. There was no evidence of drug accumulation after multiple doses. On-treatment adverse events (AEs) occurred in 19 of 43 patients in study 1 and in 11 of 17 patients in study 2. Serious AEs occurred in two patients in study 1 (gastroenteritis in one patient and acute gastroenteritis from rota virus infection resulting in discontinuation of one patient); the serious AEs resolved and were not considered by the investigators to be drug related. No other safety-related discontinuations occurred in either study.
Conclusions: Exposure increased with increasing doses of pantoprazole granules, even though wide inter-individual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar in study 1 and slightly lower in study 2. Pantoprazole was generally well tolerated in infants and children aged 1 month through <6 years with GORD.
KeywordsRota Virus Lansoprazole Esomeprazole Pantoprazole Apple Juice
The authors thank Tuli Ahmed, medical writer, for professional medical writing assistance, which was funded by Wyeth Research. Wyeth was acquired by Pfizer Inc. in October 2009. The authors acknowledge Wyeth Research, the sponsor, for designing and conducting these studies. Investigators collected the data, Wyeth Research conducted the analyses, and the authors conducted the data interpretation. J.E. Sullivan, K.G. Adcock, M.A. Springer, J. Kierkus, J. Giblin and R.M. Ward were investigators in the studies, and their institutions received compensation from Wyeth Research. Dr Sullivan’s participation was supported by National Institute of Child Health and Human Development (NICHD) grant #U10 HD045986. Dr Ward’s participation was supported in part by NICHD Pediatric Pharmacology Research Network grant #U10 HD045986. The remaining authors were employees of Wyeth Research at the time of the study and employees of Wyeth Research and Pfizer Inc. during the time of manuscript preparation. All authors approved the final manuscript and made the decision to submit the manuscript for publication. In addition to Pfizer authors, other designated Pfizer employees reviewed the manuscript.
Clinical Investigators: The following investigators enrolled ≥1 patient in the pharmacokinetic portion of study 1 and enrolled ≥1 patient aged <6 years in study 2: Phyllis R. Bishop (University of Mississippi Medical Center, Jackson, MS, USA; studies 1 and 2); Krysztof Fyderek (Krakowie Klinika Pediatrii, Gastroenterologii Zywienia Ul Wielicka, Uniwersytecki Szpital Dzieciecy W, Krakow, Poland; study 1); John M. Giblin (Clinical Study Centers, LLC, Little Rock, AR, USA; studies 1 and 2); Thirumazhisai S. Gunasekaran (Advocate Lutheran General Children’s Hospital, Park Ridge, IL, USA; studies 1 and 2); Sandeep Gupta (James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis, IN, USA; study 2); Mitchell H. Katz (Children’s Hospital of Orange County, Orange, CA, USA; study 2); Jaroslaw Kierkus (Department of Gastroenterology, Hepatology and Immunology, Children’s Memorial Health Institute, Warsaw, Poland; study 1); Alan Sacks (Division of Gastroenterology, Nemours Children’s Clinic, Pensacola, FL, USA; studies 1 and 2); Margaret Ann Springer (Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA; study 1); Janice E. Sullivan (Kosair Charities Pediatric Clinical Research Unit, University of Louisville, Louisville, KY, USA; studies 1 and 2); Neelesh A. Tipnis (Medical College of Wisconsin, Milwaukee, WI, USA; study 2); Philip Toltzis (University Hospitals of Cleveland, Cleveland, OH, USA; study 1); Robert Ward (Primary Children’s Medical Center, University of Utah, Salt Lake City, UT, USA; study 2); and Harland S. Winter (Pediatric GI Unit, Massachusetts General Hospital, Boston, MA, USA; study 2).
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