Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats

Author:

Melillo Nicola12,Scotcher Daniel1ORCID,Kenna J. Gerry3,Green Claudia4,Hines Catherine D. G.5,Laitinen Iina67,Hockings Paul D.78ORCID,Ogungbenro Kayode1,Gunwhy Ebony R.9ORCID,Sourbron Steven9,Waterton John C.310ORCID,Schuetz Gunnar4,Galetin Aleksandra1ORCID

Affiliation:

1. Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Science, The University of Manchester, Manchester M13 9PL, UK

2. SystemsForecastingUK Ltd., Lancaster LA1 5DD, UK

3. Bioxydyn Ltd., Manchester M15 6SZ, UK

4. MR & CT Contrast Media Research, Bayer AG, 13353 Berlin, Germany

5. GSK, Collegeville, PA 19426, USA

6. Sanofi-Aventis Deutschland GmbH, Bioimaging Germany, 65929 Frankfurt am Main, Germany

7. Antaros Medical, 431 83 Mölndal, Sweden

8. MedTech West, Chalmers University of Technology, 413 45 Gothenburg, Sweden

9. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TA, UK

10. Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, The University of Manchester, Manchester M13 9PL, UK

Abstract

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.

Funder

Innovative Medicines Initiatives 2 Joint Undertaking

Publisher

MDPI AG

Subject

Pharmaceutical Science

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