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

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.

Physiologically based pharmacokinetic (PBPK) modelling of oral drug absorption in older adults - an AGePOP review.

The older population consisting of persons aged 65 years or older is the fastest-growing population group and also the major consumer of pharmaceutical products. Due to the heterogenous ageing process, this age group shows high interindividual variability in the dose-exposure-response relationship and, thus, a prediction of drug safety and efficacy is challenging. Although physiologically based pharmacokinetic (PBPK) modelling is a well-established tool to inform and confirm drug dosing strategies during drug development for special population groups, age-related changes in absorption are poorly accounted for in current PBPK models. The purpose of this review is to summarise the current state-of-knowledge in terms of physiological changes with increasing age that can influence the oral absorption of dosage forms. The capacity of common PBPK platforms to incorporate these changes and describe the older population is also discussed, as well as the implications of extrinsic factors such as drug-drug interactions associated with polypharmacy on the model development process. The future potential of this field will rely on addressing the gaps identified in this article, which can subsequently supplement in-vitro and in-vivo data for more robust decision-making on the adequacy of the formulation for use in older adults and inform pharmacotherapy.