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

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.