A Bayesian approach for population pharmacokinetic modelling of sirolimus

Abstract

To explore a Bayesian approach for the pharmacokinetic analysis of sirolimus concentration data arising from therapeutic drug monitoring (poorly informative concentration-time point design), and to explore possible covariate relationships for sirolimus pharmacokinetics. Sirolimus concentration-time data were available as part of routine clinical care from 25 kidney transplant recipients. Most samples were taken at or near the trough time point at steady state. The data were analyzed using a fully conditional Bayesian approach with PKBUGS (v 1.1)/WinBUGS (v 1.3). Features of the data included noncompliance and missing concentration measurements below the limit of sensitivity of the assay. Informative priors were used. A two-compartment model with proportional residual error provided the best fit to the data (consisting of 315 sirolimus concentration-time points). The typical value for the apparent clearance (CL/F ) was 12.5 l h(-1) at the median age of 44 years. Apparent CL was found to be inversely related to age with a posterior probability of a clinically significant effect of 0.734. A population pharmacokinetic model was developed for sirolimus using a novel approach. Bayesian modelling with informative priors allowed interpretation of a significant covariate relationship, even using poorly informative data.