A Pharmacokinetic Study of Ranitidine in a Paediatric Population
P. Westwood, P. Collier, S. Yakkundi
School of Pharmacy, Faculty of Medicine, Health and Life Sciences, Queen’s University of Belfast, Northern Ireland, United Kingdom
Objectives: Ranitidine is a histamine-2-receptor-antagonist widely used in intensive care units as prophylaxis against stress ulcer syndrome, gastro oesophageal reflux, persistent vomiting and gastric aspiration, or to negate the harmful effects of steroids. The purpose of this study was to use sparse data to investigate the pharmacokinetic (PK) profile of both i.v. (infusion and intermittent bolus dosing) and oral ranitidine in a paediatric population and to determine the influence of patient demographics; age, gender, weight, concomitant drugs and disease states.
Methods: The population PK analysis was performed in NONMEM (v.6.1). Several models were tested including one- and two-compartment disposition and double peak absorption models. Influence of the patient demographics was assessed as both continuous and categorical covariates. Development of the final model was guided by the relevant plots, reduction in the errors, and the change in the objective function using a multi-stage forward and backward stepwise elimination modeling approach. Three methods were used to evaluate the final model for the ranitidine dataset; a variation on the Jack-Knifing technique, Bootstrapping and Principal Component Analysis.
Results: Data from 78 children attending The Royal Belfast Hospital for Sick Children between 1998 and 2006 (mean age 4.57±4.48 years and mean weight 16.27±12.24kg) provided 248 opportunistically drawn samples with a median of 2 samples per patient (range 1 to 13). Conditions were separated into five main categories including stomach surgery and management of heart defects. There were 247 concomitant drug therapies identified from the individual patient records. A one compartment model best described the data. The final parameter estimates for the population were 32.1L/hr (CV 60%) for total clearance and 285L (CV 85%) for volume, both allometrically scaled for a 70kg adult and final estimates for the typical absorption rate constant and bioavailability of 1.31hr-1 and 27.5%, respectively. Weight was the most significant covariate in the model and the presence of heart-related conditions was shown to significantly reduce ranitidine clearance by 54%.
Conclusions: This PK study of ranitidine in a paediatric population found that the presence of a heart condition significantly decreased the clearance, and dose adjustments and careful monitoring are recommended for paediatric patients with heart conditions who are receiving ranitidine.