Analyzing parametric influences driving age-associated changes in absorption using a PBPK-GSA approach

Abstract

The advanced age population may be susceptible to an increased risk of adverse effects due to increased drug exposure after oral dosing. Factors such as high-interindividual variability and lack of data has led to poor characterization of absorption's role in pharmacokinetic changes in this population. Physiologically based pharmacokinetic (PBPK) models are increasingly being used during the drug development process, as their unique qualities are advantageous in atypical scenarios such as drug-drug interactions or special populations such as older people. Along with relying on various sources of data, auxiliary tools including parameter estimation and sensitivity analysis techniques are employed to support model development and other applications. However, sensitivity analyses have mostly been limited to localized techniques in the majority of reported PBPK models using them. This is disadvantageous, since local sensitivity analyses are unsuitable for risk analysis, which require assessment of parametric interactions and proper coverage of the input space to better estimate and subsequently mitigate the effects of the phenomenon of interest. For this reason, this study seeks to integrate a global sensitivity analysis screening method with PBPK models based in PK-Sim® to characterize the consequences of potential changes in absorption that are often associated with advanced age. The Elementary Effects (Morris) method and visualization of the results are implemented in R and three model drugs representing Biopharmaceutical Classification System classes I-III that are expected to exhibit some sensitivity to three age-associated hypotheses were successfully tested.