Physiologically Based Pharmacokinetic Modelling to Identify Physiological and Drug Parameters Driving Pharmacokinetics in Obese Individuals.

Berton, Mattia ORCID: 0000-0001-9450-2228, Bettonte, Sara ORCID: 0000-0002-7532-7898, Stader, Felix, Battegay, Manuel and Marzolini, Catia ORCID: 0000-0002-2312-7050 (2023) Physiologically Based Pharmacokinetic Modelling to Identify Physiological and Drug Parameters Driving Pharmacokinetics in Obese Individuals. Clinical pharmacokinetics, 62 (2). pp. 277-295.

Access the full-text of this item by clicking on the Open Access link.

Official URL: http://dx.doi.org/10.1007/s40262-022-01194-3

Abstract

<h4>Background</h4>Obese individuals are often underrepresented in clinical trials, leading to a lack of dosing guidance.<h4>Objective</h4>This study aimed to investigate which physiological parameters and drug properties determine drug disposition changes in obese using our physiologically based pharmacokinetic (PBPK) framework, informed with obese population characteristics.<h4>Methods</h4>Simulations were performed for ten drugs with clinical data in obese (i.e., midazolam, triazolam, caffeine, chlorzoxazone, acetaminophen, lorazepam, propranolol, amikacin, tobramycin, and glimepiride). PBPK drug models were developed and verified first against clinical data in non-obese (body mass index (BMI) ≤ 30 kg/m<sup>2</sup>) and subsequently in obese (BMI ≥ 30 kg/m<sup>2</sup>) without changing any drug parameters. Additionally, the PBPK model was used to study the effect of obesity on the pharmacokinetic parameters by simulating drug disposition across BMI, starting from 20 up to 60 kg/m<sup>2</sup>.<h4>Results</h4>Predicted pharmacokinetic parameters were within 1.25-fold (71.5%), 1.5-fold (21.5%) and twofold (7%) of clinical data. On average, clearance increased by 1.6% per BMI unit up to 64% for a BMI of 60 kg/m<sup>2</sup>, which was explained by the increased hepatic and renal blood flows. Volume of distribution increased for all drugs up to threefold for a BMI of 60 kg/m<sup>2</sup>; this change was driven by pK<sub>a</sub> for ionized drugs and logP for neutral and unionized drugs. C<sub>max</sub> decreased similarly across all drugs while t<sub>max</sub> remained unchanged.<h4>Conclusion</h4>Both physiological changes and drug properties impact drug pharmacokinetics in obese subjects. Clearance increases due to enhanced hepatic and renal blood flows. Volume of distribution is higher for all drugs, with differences among drugs depending on their pK<sub>a</sub>/logP.

Item Type:	Article
Uncontrolled Keywords:	Humans, Obesity, Propranolol, Midazolam, Caffeine, Body Mass Index, Pharmacokinetics, Models, Biological, Computer Simulation
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	29 Feb 2024 09:20
Last Modified:	29 Feb 2024 09:20
DOI:	10.1007/s40262-022-01194-3
Open Access URL:	https://doi.org/10.1007/s40262-022-01194-3
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178995