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Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice


Taddio, Marco F; Mu, Linjing; Keller, Claudia; Schibli, Roger; Krämer, Stefanie D (2018). Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice. Contrast media & molecular imaging, 2018:5849047.

Abstract

Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict pharmacokinetics based on physiological parameters and data from studies and assays. PBPK modelling in laboratory animals by noninvasive imaging could help to improve the translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [C]AM7 and [C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([C]AM7 = 2; [C]MT107, = 4) and after administration of cyclosporine ([C]MT107, = 4). The modelling revealed a significant reduction in [C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 l/min after cyclosporine administration. The excretion profile of [C]MT107 was shifted from predominantly hepatobiliary (CL/CL = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CL/CL = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the effects of transporter inhibition on whole-body and organ-specific pharmacokinetics.

Abstract

Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict pharmacokinetics based on physiological parameters and data from studies and assays. PBPK modelling in laboratory animals by noninvasive imaging could help to improve the translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [C]AM7 and [C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([C]AM7 = 2; [C]MT107, = 4) and after administration of cyclosporine ([C]MT107, = 4). The modelling revealed a significant reduction in [C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 l/min after cyclosporine administration. The excretion profile of [C]MT107 was shifted from predominantly hepatobiliary (CL/CL = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CL/CL = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the effects of transporter inhibition on whole-body and organ-specific pharmacokinetics.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nuclear Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2018
Deposited On:04 Dec 2018 15:01
Last Modified:24 Sep 2019 23:54
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1555-4309
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1155/2018/5849047
PubMed ID:29967572

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