Prophylactic ranitidine treatment in critically ill children – a population pharmacokinetic study

Abstract

AIMSTo characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. METHODSData were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. RESULTSA one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h -1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h -1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. CONCLUSIONSCurrently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Evaluation of Intravenous Ranitidine on Gastric pH in Critically Ill Pediatric Patients

“…The result interpretation and documentation of the pH were the responsibility of the bedside nurse, which encompassed a large group of health care providers and a potentially greater range of error. 5,6,8,17 Despite this, our results are in concert with these previous studies. Our study reflects the practice of monitoring gastric pH that is common in pediatric intensive care and would likely be used to titrate therapy, as opposed to more invasive monitoring.…”

“…8 Similarly, other studies have noted that dosing every 6 hours and/or a continuous infusion of IVR is required to consistently maintain goal gastric pH values in critically ill pediatric patients. 5,[17][18][19] Based on prior publications and our own analysis, a dosing interval of every 6 hours for bolus dosing of IVR in pediatric critical illness would be necessary to have the highest probability of attainment of a gastric pH ≥4.…”

The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis

“…When patient demographic characteristics were assessed for effect on the population parameters, body size expressed as total body weight was found to be superior to other size descriptors (including height, BMI, BSA and age) and was therefore included in the model as the only significant variable affecting the population CL, V 1 , V 2 and Q. Allometric size adjustment, with fixed exponents of 0.75 for clearance and 1 for volume of distribution, was used for inclusion of weight in the current model because the method is well established and has a strong scientific and physiological basis [18,19]. Furthermore, such an approach is useful to describe age‐related difference and has been adopted by many researchers during development of population pharmacokinetic models in children [20–23]. As indicated in the current PK models for all forms of ketorolac population, parameters including CL were significantly correlated to the child's weight by use of allometric scaling.…”

Pharmacokinetics and pharmacodynamics of famotidine and ranitidine in critically ill children

“…Altered biodisposition of H2 receptor blockers in children compared to adults has been demonstrated secondary to immature hepatic and renal function . In addition to effects of immaturity, children in PICU often have organ function compromised by disease, further affecting pharmacokinetics and pharmacodynamics of drug therapy . A paucity of data persists regarding the comparative efficacy and pharmacokinetics of these agents in a PICU population.…”