A Meta-Analysis Methodology in Stan to Estimate Population Pharmacokinetic Parameters from Multiple Aggregate Concentration–Time Datasets: Application to Gevokizumab mPBPK Model

Abstract

The aim of the present study was to develop and evaluate the performance of a methodology to estimate the population pharmacokinetic (PK) parameters along with the inter-individual variabilities (IIVs) from patients’ reported aggregate concentration–time data, in particular, mean plasma concentrations and their standard deviations (SDs) versus time, such as those often found in published graphs. This method was applied to the published data of gevokizumab, a novel monoclonal anti-interleukin-1β antibody, in order to estimate the drug’s population pharmacokinetic (PopPK) parameters of a second-generation minimal physiologically based pharmacokinetic (mPBPK) model. Assuming this mPBPK model, a mixed effects approach was utilized to allow accounting for the random inter-group variability (IGV) that was assumed among different dosage groups. The entire analysis was performed using R software (Rstudio) and the Bayesian software tool RStan was used for the application of Bayesian priors on the parameters. Conclusively, the proposed method could be applied to monoclonal antibodies for which the second-generation mPBPK model has been proposed as well as to other drugs with different PK models when only a published graph with aggregate concentration–time data is available. In addition, the method could be used when multiple aggregate datasets from different sources need to be combined in a meta-analysis approach in order to estimate the PopPK parameters of a drug.

Keywords

• aggregate concentration-time data
• population pharmacokinetic parameters
• gevokizumab
• RStan
• meta-analysis