Population pharmacokinetics of intravenous pantoprazole in paediatric intensive care patients

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit.• Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce. WHAT THIS STUDY ADDS• Our population approach has determined the pharmacokinetic parameters of intravenous pantoprazole in paediatric intensive care patients and the relative importance of factors influencing its disposition.• Pantoprazole clearance was significantly influenced by developmental changes and by the presence of systemic inflammatory syndrome, hepatic dysfunction and CYP2C19 inhibitors. AIMSTo characterize the pharmacokinetics of intravenous pantoprazole in a paediatric intensive care population and to determine the influence of demographic factors, systemic inflammatory response syndrome (SIRS), hepatic dysfunction and concomitantly used CYP2C19 inducers and inhibitors on the drug's pharmacokinetics. METHODSA total of 156 pantoprazole concentration measurements from 20 patients (10 days to 16.4 years of age) at risk for or with upper gastrointestinal bleeding, who received pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m 2 /day, were analysed using a population pharmacokinetic approach (NONMEM program). RESULTSThe best structural model for pantoprazole was a two-compartment model with zero order infusion and first-order elimination. Body weight, SIRS, age, hepatic dysfunction and presence of CYP2C19 inhibitors were significant covariates affecting clearance (CL), accounting for 75% of interindividual variability. Only body weight significantly influenced central volume of distribution (Vc). In the final population model, the estimated CL and Vc were 5.28 l h -1 and 2.22 l, respectively, for a typical 5-year-old child weighing 20 kg. Pantoprazole CL increased with weight and age, whereas the presence of SIRS, CYP2C19 inhibitors and hepatic dysfunction, when present separately, significantly decreased pantoprazole CL by 62.3, 65.8 and 50.5%, respectively. For patients aged between 6 months and 5 years without SIRS, CYP2C19 inhibitor or hepatic dysfunction, the predicted pantoprazole CL is faster than that reported in adults. CONCLUSIONThese results provide important information for physicians regarding selection of a starting dose and dosing regimens of pantoprazole for paediatric intensive care patients based on factors frequently encountered in this population.

Population Pharmacokinetic Modeling of Pantoprazole in Pediatric Patients From Birth to 16 Years

“…The typical population pharmacokinetic parameters from the final model were similar to recent articles investigating the pharmacokinetics of pantoprazole in pediatrics 10 , 31 . The typical CL fell between the reported mean values (1.4 L per hour and 3.0 L per hour), while the volume of distribution at steady‐state (V2 + V3) was lower than the reported mean values (2.2 L and 2.5 L) for these 2 studies.…”

“…There is limited information regarding the pharmacokinetics of pantoprazole in children. Recently published studies were either limited to single doses of intravenous (IV) or oral pantoprazole, or investigated only IV pantoprazole in a small number (n = 20) of pediatric patients 9 , 10 . The pharmacokinetic characteristics of pantoprazole (linear, short half‐life, lack of drug interactions) make it an attractive agent for pediatric use 11 – 13 .…”

Gastro-Esophageal Reflux Disease in Healthy Older Children and Adolescents

“…The dosage of each PPI varies per weight and age as they are rapidly absorbed and metabolized: esomeprazole (0.2-1 mg/kg/day, 1-17 years), omeprazole (0.7-3.5 mg/kg/day, 2-16 years), lansoprazole (0.7-1.44 mg/kg/day, 1-17 years), pantoprazole (0.6-1.2 mg/kg/day) [33-36]. PPI does not develop tachyphylaxis [36]. All kinds of PPIs have similar anti-secretory effects.…”

Pharmacokinetics of intravenous omeprazole in critically ill paediatric patients

“…Those authors found that the clearance of pantoprazole increased with increasing weight and age, and fell with the presence of SIRS, CYP2C19 inhibitors, and liver dysfunction. However, in patients between 6 months and 5 years of age without these factors, pantoprazole clearance was higher than in adults [44].…”