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

Stader, Felix, Kinvig, Hannah ORCID: 0000-0002-0061-1683, Penny, Melissa A, Battegay, Manuel, Siccardi, Marco ORCID: 0000-0002-3539-7867 and Marzolini, Catia (2020) Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly. CLINICAL PHARMACOKINETICS, 59 (3). pp. 383-401.

Text
Stader et al. (2019)_ClinPK_PK_Aging.docx - Author Accepted Manuscript
Download (3MB)

Official URL: http://dx.doi.org/10.1007/s40262-019-00822-9

Abstract

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>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 [C<sub>max</sub>], time to C<sub>max</sub> [t<sub>max</sub>], 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.<h4>Results</h4>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 C<sub>max</sub>, t<sub>max</sub> 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.<h4>Conclusion</h4>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.

Item Type:	Article
Uncontrolled Keywords:	Liver, Kidney, Humans, Hypnotics and Sedatives, Antihypertensive Agents, Anticholesteremic Agents, Hypoglycemic Agents, Anti-Bacterial Agents, Antibiotics, Antitubercular, Area Under Curve, Sensitivity and Specificity, Aging, Regional Blood Flow, Models, Theoretical, Aged, Aged, 80 and over, Female, Male, Clinical Trials as Topic, Factor Xa Inhibitors
Depositing User:	Symplectic Admin
Date Deposited:	02 Jan 2020 16:15
Last Modified:	19 Jan 2023 00:11
DOI:	10.1007/s40262-019-00822-9
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3068850