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Daniel Scotcher, Sirisha Tadimalla, Adam Darwich, Sabina Ziemian, Kayode Ogungbenro, Gunnar Schütz, Steven Sourbron, Aleksandra Galetin

ISSX conference 2019.

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides a framework for in vitro-in vivo extrapolation (IVIVE) of drug disposition. However, prediction of transporter-mediated processes and tissue permeation remains challenging due to the lack of available in vivo tissue data for validation. Gadoxetate is a magnetic resonance imaging (MRI) contrast agent used clinically for hepatic lesion characterisation. As a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2), gadoxetate is being explored as a novel imaging biomarker for hepatic transporter function in context of evaluation of drug-drug interactions and drug induced liver injury [1]. The current study aimed to characterise uptake kinetics of gadoxetate in plated rat hepatocytes and develop a PBPK model to predict gadoxetate in vivo plasma and liver exposure. In vitro uptake was measured by incubating rat hepatocytes with 0.01 – 10mM gadoxetate for 0.5 – 150 min. Relevant in vitro transporter kinetic parameters were derived using a mechanistic cell model [2]. Subsequently, a novel PBPK model was developed for gadoxetate in rat, where liver uptake and cellular binding were informed by IVIVE. Gadoxetate in vivo blood, spleen and liver data obtained in the presence (n=9) and absence (n=27) of a single 10 mg/kg intravenous dose of rifampicin [3] were used for PBPK model validation/refinement. In vitro gadoxetate uptake affinity constant (Km) obtained in rat hepatocytes was 0.106 mM (n=4 rats), with saturable active transport accounting for 94% of gadoxetate cellular uptake; bidirectional transport, not saturable under current experimental conditions, was minor. The fraction unbound in hepatocytes was estimated to be 0.65. The total (Kp,u) and unbound (Kp,uu) hepatocyte:media partition coefficients were 26.0 and 16.9, respectively. The PBPK model successfully predicted gadoxetate concentrations in systemic blood and spleen and corresponding 2-fold increase in gadoxetate systemic exposure in the presence of rifampicin. In contrast, liver concentrations were under-predicted. Refinement of the PBPK model using the dynamic contrast agent enhanced (DCE)-MRI data enabled recovery of the liver profile, assuming complete and partial inhibition of hepatic uptake and biliary efflux by rifampicin, respectively. The current study demonstrates utility of imaging data in validating and refining PBPK models for prediction of transporter-mediated disposition; considerations of interpretation of quantitative DCE-MRI data to inform PBPK models are discussed.