Modeling of trough plasma bismuth concentrations

Abstract

Disposition pharmacokinetics of bismuth following oral dosing of ranitidine bismuth citrate are complicated and variable. An analysis of data from healthy volunteers suggests a model with three disposition compartments and first-order absorption. Patient data are pooled from 10 separate studies and consist of 1140 trough concentrations measured in 802 patients following dosing of 2 to 12 weeks duration. There are therefore insufficient data to obtain reliable parameter estimates for the full model and we use instead a much reduced model and an informative prior based on the volunteer data. Individual parameter estimates from this model can then be used to establish covariate relationships. Trough concentrations were influenced by the coadministration of clarithromycin and by creatinine clearance. A simulation study was carried out to check the validity of the estimates obtained from the reduced model. We carry out analysis via Bayesian sampling-based techniques. Throughout, we use predictive distributions for both diagnostic and inference purposes. In particular, we determine predicted distributions for the Cmax, Cmin and AUC characteristics of new individuals.