Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
Journal article, 2023
Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (khe), and biliary excretion (kbh). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate khe and kbh by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in khe (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97–98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans.
hepatic transporters
DCE-MRI
OATP1B
pharmacokinetics
modelling and simulation
gadoxetate
Author
Nicola Melillo
SystemsForecastingUK Ltd.
Faculty of Biology, Medicine and Health
Daniel Scotcher
Faculty of Biology, Medicine and Health
J. Gerry Kenna
Bioxydyn Limited
Claudia Green
Bayer AG
Catherine D.G. Hines
GlaxoSmithKline, USA
Iina Laitinen
Antaros Medical AB
Sanofi-Aventis Deutschland GmbH
Paul Hockings
Chalmers, Electrical Engineering, Signal Processing and Biomedical Engineering
Antaros Medical AB
Kayode Ogungbenro
Faculty of Biology, Medicine and Health
Ebony R. Gunwhy
University of Sheffield
Steven Sourbron
University of Sheffield
John C Waterton
Bioxydyn Limited
Faculty of Biology, Medicine and Health
Gunnar Schuetz
Bayer AG
Aleksandra Galetin
Faculty of Biology, Medicine and Health
Pharmaceutics
19994923 (eISSN)
Vol. 15 3 896Subject Categories
Pharmaceutical Sciences
Oceanography, Hydrology, Water Resources
Radiology, Nuclear Medicine and Medical Imaging
DOI
10.3390/pharmaceutics15030896