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

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.

 

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The study investigated the effect of six drugs on the transport of gadoxetate, an MRI contrast agent, in rats. The drugs were tested for their ability to inhibit the organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2 transporters. The study used physiologically-based pharmacokinetic (PBPK) modelling to predict changes in gadoxetate systemic and liver AUC (AUCR) resulting from transporter modulation.

The study found that ciclosporin and rifampicin caused significant decreases in gadoxetate liver AUC, while asunaprevir, bosentan, and pioglitazone caused marginal changes. Unexpectedly, ketoconazole decreased both systemic and liver gadoxetate AUCs. The study used a tracer-kinetic model to estimate rate constants for hepatic uptake and biliary excretion of gadoxetate. Ciclosporin and rifampicin decreased gadoxetate khe and kbh, with ciclosporin causing a 96% decrease in khe. PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, but underpredicted decreases in liver AUCs.

The study demonstrates a framework for integrating liver imaging data, PBPK modelling, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated drug-drug interactions in humans.

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S4935 Asunaprevir Asunaprevir is an orally bioavailable inhibitor of the hepatitis C virus enzyme serine protease NS3 that is necessary for protein processing required for viral replication.

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HCV Protease