Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Systems Biology and Modeling
• Drug Discovery and Development

Background:

• Drug-drug interactions (DDIs) mediated by hepatic transporters significantly impact drug efficacy and safety.
• Organic anion transporting polypeptides (OATPs) are crucial for the uptake of many drugs, including statins.
• Physiologically based pharmacokinetic (PBPK) modeling offers a powerful tool for predicting DDIs.

Purpose of the Study:

• To develop a widely applicable PBPK modeling method for quantitative analysis of DDIs involving OATP inhibition.
• To incorporate enterohepatic circulation (EHC) of statins into PBPK models for improved accuracy.
• To optimize PBPK parameters using clinical data for various statin substrates and known OATP inhibitors.

Main Methods:

• Construction of PBPK models for pitavastatin, fluvastatin, and pravastatin as OATP substrates.
• Inclusion of cyclosporin A (CsA) and rifampicin (RIF) as OATP inhibitors in the PBPK models.
• Optimization of absorption, hepatic elimination, and EHC parameters by fitting to clinical data.

Main Results:

• The developed PBPK models satisfactorily explained the extent of DDIs caused by OATP inhibition.
• Consistent in vivo inhibition constant (Ki) values were obtained for each inhibitor across different statin substrates.
• Estimated Ki values for CsA aligned with in vitro data, while RIF values were lower than reported in vitro values.

Conclusions:

• This study proposes a robust method for optimizing in vivo PBPK parameters in transporter-mediated DDIs.
• The PBPK modeling approach provides a valuable framework for predicting OATP-mediated DDIs.
• The findings contribute to a better understanding of statin pharmacokinetics and drug interactions.