The first two authors contributed equally to this work.
Prophylactic ranitidine treatment in critically ill children – a population pharmacokinetic study
Article first published online: 8 APR 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 5, pages 1265–1276, May 2013
How to Cite
Hawwa, A. F., Westwood, P. M., Collier, P. S., Millership, J. S., Yakkundi, S., Thurley, G., Shields, M. D., Nunn, A. J., Halliday, H. L. and McElnay, J. C. (2013), Prophylactic ranitidine treatment in critically ill children – a population pharmacokinetic study. British Journal of Clinical Pharmacology, 75: 1265–1276. doi: 10.1111/j.1365-2125.2012.04473.x
- Issue published online: 8 APR 2013
- Article first published online: 8 APR 2013
- Accepted manuscript online: 28 SEP 2012 06:26AM EST
- Manuscript Accepted: 10 AUG 2012
- Manuscript Received: 9 FEB 2012
- Action Medical Research
- Health and Social Care Research and Development office (N. Ireland)
- gastro-oesophageal reflux;
- nonlinear mixed-effects modelling;
- population pharmacokinetics;
- stress ulcers
To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition.
Data 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.
A 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.
Currently, 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.