Implementation of Oral Drug Absorption in Older Adults in the Physiologically Based Pharmacokinetic (PBPK) Modelling Platforms
Cleo Demeester
Bayer AG and KU Leuven
Objectives: 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 aging 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 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 software. This research aims to characterise the incorporation of physiological changes caused by increasing age that can influence the oral absorption of dosage forms in the PBPK software.
Methods: The representatives of PBPK modelling platforms OSP (PK-Sim), SimCyp, and GastroPlus filled in a questionnaire concerning the parameterization of absorption in their respective older adult databases.
Results: Stomach acid output, saliva flow rate, saliva pH, jejunum pH, ileum pH, cecum pH, ascending and descending colon pH, active transporter concentrations, gastrointestinal enzyme concentrations, and gastrointestinal fluid volumes can be manually adapted in the different software but do not incorporate standard changes in the older population database of all three platforms. Also, no age-dependent variability is incorporated in the different platforms for these parameters. Simcyp and OSP additionally did not inform the stomach pH, duodenum pH, gastric emptying time, small and large intestinal transit time, micelle-mediated solubility, and bile salts concentrations. GastroPlus did inform these parameters but concluded that the literature shows no significant differences between the young adult population and the older adult population, meaning that they kept the same parameter value as for the younger adult population. Besides, none of the software incorporates the effect of the gut microbiome for different age groups. Food effects were handled differently in every software. Simcyp incorporated a slower rate of return for the stomach pH after a meal in the older population. GastroPlus and OSP did not report or include an age-informed rate of return to fasted pH in the absorption model, respectively, meaning the return rate for young adults implemented in the software, is the same as for the older population.
Conclusions:
This questionnaire led to the conclusion that the impact of age on a number of gastrointestinal physiological parameters is not yet fully accounted for in the various modelling software. Some information for these parameters, such as gastric pH, was gathered from the literature and incorporated into the software, but for others, such as active transport, more research is required. The future potential of these results relies on awareness of the gaps identified, 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.
