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Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly

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Abstract

Background

Medication use is highly prevalent with advanced age, but clinical studies are rarely conducted in the elderly, leading to limited knowledge regarding age-related pharmacokinetic changes.

Objective

The objective of this study was to investigate which pharmacokinetic parameters determine drug exposure changes in the elderly by conducting virtual clinical trials for ten drugs (midazolam, metoprolol, lisinopril, amlodipine, rivaroxaban, repaglinide, atorvastatin, rosuvastatin, clarithromycin and rifampicin) using our physiologically based pharmacokinetic (PBPK) framework.

Methods

PBPK models for all ten drugs were developed in young adults (20–50 years) following the best practice approach, before predicting pharmacokinetics in the elderly (≥ 65 years) without any modification of drug parameters. A descriptive relationship between age and each investigated pharmacokinetic parameter (peak concentration [Cmax], time to Cmax [tmax], area under the curve [AUC], clearance, volume of distribution, elimination-half-life) was derived using the final PBPK models, and verified with independent clinically observed data from 52 drugs.

Results

The age-related changes in drug exposure were successfully simulated for all ten drugs. Pharmacokinetic parameters were predicted within 1.25-fold (70%), 1.5-fold (86%) and 2-fold (100%) of clinical data. AUC increased progressively by 0.9% per year throughout adulthood from the age of 20 years, which was explained by decreased clearance, while Cmax, tmax and volume of distribution were not affected by human aging. Additional clinical data of 52 drugs were contained within the estimated variability of the established age-dependent correlations for each pharmacokinetic parameter.

Conclusion

The progressive decrease in hepatic and renal blood flow, as well as glomerular filtration, rate led to a reduced clearance driving exposure changes in the healthy elderly, independent of the drug.

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Authors and Affiliations

  1. Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland

    Felix Stader, Manuel Battegay & Catia Marzolini

  2. Infectious Disease Modelling Unit, Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland

    Felix Stader & Melissa A. Penny

  3. University of Basel, Basel, Switzerland

    Felix Stader, Melissa A. Penny, Manuel Battegay & Catia Marzolini

  4. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Hannah Kinvig & Marco Siccardi

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  1. Felix Stader
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  2. Hannah Kinvig
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Correspondence to Felix Stader.

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Funding

This study was supported by the Swiss National Foundation (Grant number 166204), the OPO Foundation, and the Isaac Dreyfus Foundation. Melissa A. Penny was additionally supported by the Swiss National Foundation Professorship (PP00P3 170702).

Conflict of interest

Felix Stader, Hannah Kinvig, Melissa A. Penny, Manuel Battegay, Marco Siccardi, and Catia Marzolini have no conflicts of interest to declare.

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Stader, F., Kinvig, H., Penny, M.A. et al. Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly. Clin Pharmacokinet 59, 383–401 (2020). https://doi.org/10.1007/s40262-019-00822-9

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