Effect of Ritonavir on (99m)Technetium-Mebrofenin Disposition in Humans: A Semi-PBPK Modeling and In Vitro Approach...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Hepatobiliary Transport
• Drug-Drug Interactions

Background:

• Hepatobiliary imaging agents like 99mTc-mebrofenin are subject to complex transport mechanisms.
• Drug-drug interactions (DDIs) involving transporter inhibition can alter drug exposure and efficacy.
• Understanding ritonavir's impact on 99mTc-mebrofenin disposition is crucial for clinical safety.

Purpose of the Study:

• To develop a semiphysiologically based pharmacokinetic (semi-PBPK) model for 99mTc-mebrofenin.
• To investigate the mechanisms of a 99mTc-mebrofenin-ritonavir DDI using clinical and in vitro data.
• To assess the role of hepatic uptake and biliary excretion in this DDI.

Main Methods:

• Development of a semi-PBPK model incorporating unique clinical data (blood, liver, bile).
• In vitro studies using human sandwich-cultured hepatocytes (SCH) to determine ritonavir's inhibitory potential (IC50).
• Simulation of DDIs using integrated modeling, clinical, and in vitro data.

Main Results:

• Ritonavir significantly increased systemic 99mTc-mebrofenin exposure (4,464 vs. 1,970 nCi min/ml).
• Ritonavir inhibited 99mTc-mebrofenin accumulation in SCH with an IC50 of 3.46 µmol/l.
• Modeling indicated ritonavir inhibited hepatic uptake but not MRP2-mediated biliary excretion of 99mTc-mebrofenin.

Conclusions:

• Ritonavir's DDI with 99mTc-mebrofenin primarily involves inhibition of hepatic uptake.
• Extensive intracellular binding of ritonavir limited its impact on MRP2-mediated biliary excretion.
• Assessing transporter-mediated hepatic DDIs requires consideration of hepatic/extrahepatic distribution and intracellular unbound concentrations.