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

• Published in: European journal of clinical pharmacology 2010-06, Vol.66 (6), p.555-561
• Main Authors: Ward, Robert M., Tammara, Brinda, Sullivan, Sandra E., Stewart, Dan L., Rath, Natalie, Meng, Xu, Maguire, Mary K., Comer, Gail M.
• Format: Article
• Language: English
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles - administration & dosage; 2-Pyridinylmethylsulfinylbenzimidazoles - adverse effects; 2-Pyridinylmethylsulfinylbenzimidazoles - blood; 2-Pyridinylmethylsulfinylbenzimidazoles - pharmacokinetics; Administration, Oral; Age Factors; Anti-Ulcer Agents - administration & dosage; Anti-Ulcer Agents - adverse effects; Anti-Ulcer Agents - blood; Anti-Ulcer Agents - pharmacokinetics; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Clinical outcomes; Clinical Trial; Clinical trials; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A - genetics; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug therapy; Esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gastroesophageal reflux; Gastroesophageal Reflux - blood; Gastroesophageal Reflux - diagnosis; Gastroesophageal Reflux - drug therapy; Gastroesophageal Reflux - ethnology; Genotype; Half-Life; Humans; Infant; Infant, Newborn; Infant, Premature - metabolism; Male; Medical sciences; Metabolic Clearance Rate; Neonatal care; Other diseases. Semiology; Pantoprazole; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Premature birth; Proton Pump Inhibitors - administration & dosage; Proton Pump Inhibitors - adverse effects; Proton Pump Inhibitors - blood; Proton Pump Inhibitors - pharmacokinetics; Time Factors; Treatment Outcome
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-010-0811-8

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.