Population pharmacokinetics of intravenous pantoprazole in paediatric intensive care patients.

摘要

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. AIMS: To 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. METHODS: A 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). RESULTS: The 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 (V(c)). In the final population model, the estimated CL and V(c) 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. CONCLUSION: These 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.