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Erschienen in: Clinical Pharmacokinetics 3/2020

04.10.2019 | Original Research Article

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

verfasst von: Felix Stader, Hannah Kinvig, Melissa A. Penny, Manuel Battegay, Marco Siccardi, Catia Marzolini

Erschienen in: Clinical Pharmacokinetics | Ausgabe 3/2020

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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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Metadaten
Titel
Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly
verfasst von
Felix Stader
Hannah Kinvig
Melissa A. Penny
Manuel Battegay
Marco Siccardi
Catia Marzolini
Publikationsdatum
04.10.2019
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 3/2020
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-019-00822-9

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