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Physiologically Based Pharmacokinetic Modelling to Identify Physiological and Drug Parameters Driving
Mattia Berton1,2, Sara Bettonte3,4, Felix Stader5
1Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland. mattia.berton@unibas.ch.
Background:
Obese individuals are often underrepresented in clinical trials, leading to a lack of dosing guidance.
Objective:
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.
Methods:
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/m2) and subsequently in obese (BMI ≥ 30 kg/m2) 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/m2.
Results:
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/m2, 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/m2; this change was driven by pKa for ionized drugs and logP for neutral and unionized drugs. Cmax decreased similarly across all drugs while tmax remained unchanged.
Conclusion:
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 pKa/logP.
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