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

Area of Science:

• Pharmacology
• Biophysics
• Medical Imaging

Background:

• Gadoxetate is an MRI contrast agent and a substrate for OATP1B1 and MRP2 transporters.
• Drug-drug interactions (DDIs) involving transporter inhibition can alter drug pharmacokinetics.
• Assessing these DDIs is crucial for patient safety and effective drug therapy.

Purpose of the Study:

• To evaluate dynamic contrast-enhanced MRI biomarkers for assessing transporter inhibition in rats.
• To prospectively predict changes in gadoxetate pharmacokinetics using physiologically-based pharmacokinetic (PBPK) modeling.
• To quantify hepatic transporter-mediated DDIs.

Main Methods:

• Six drugs with varying transporter inhibition potentials were administered to rats.
• Gadoxetate-enhanced MRI was used to assess changes in gadoxetate pharmacokinetics.
• PBPK modeling and tracer-kinetic models were employed to estimate rate constants (khe, kbh) and predict pharmacokinetic changes.

Main Results:

• Ciclosporin and rifampicin significantly decreased gadoxetate liver AUC (3.8- and 1.5-fold, respectively).
• PBPK modeling accurately predicted systemic gadoxetate AUCR changes but underpredicted liver AUC decreases.
• Observed decreases in hepatic uptake rate constant (khe) correlated well with PBPK-predicted transporter inhibition.

Conclusions:

• The study demonstrates a framework integrating liver imaging, PBPK, and tracer-kinetic models for DDI assessment.
• This approach allows for prospective quantification of hepatic transporter-mediated DDIs.
• The findings highlight the utility of dynamic contrast-enhanced MRI biomarkers in DDI studies.