Assessing transporter-mediated rifampin-linezolid interaction using physiologically-based pharmacokinetic modelling

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Biology and Modeling
• Infectious Disease Pharmacology

Background:

• Drug-drug interactions (DDIs) involving rifampin and linezolid can alter linezolid's efficacy and safety.
• Understanding the role of specific transporters, like ABCB1 and ABCG2, is crucial for predicting and managing these interactions.
• Physiologically-based pharmacokinetic (PBPK) modeling offers a quantitative approach to investigate complex DDIs.

Purpose of the Study:

• To develop and validate a PBPK model for linezolid.
• To quantitatively assess the contribution of ABCB1 and ABCG2 transporters to the rifampin-linezolid DDI.
• To predict the impact of high-dose rifampin on linezolid pharmacokinetics (PK).

Main Methods:

• A PBPK model for linezolid was constructed and verified using clinical PK data.
• A PK-SIM PBPK model for rifampin, incorporating ABCB1 and ABCG2 transporter activity, was utilized.
• PBPK simulations predicted linezolid PK during co-administration with rifampin, including high-dose scenarios.

Main Results:

• The linezolid PBPK model demonstrated good predictive performance across multiple clinical studies.
• PBPK simulations indicated that ABCB1 plays a more significant role than ABCG2 in the rifampin-linezolid DDI.
• Predicted DDI ratios for standard-dose rifampin closely matched observed clinical data.
• Increasing rifampin dosage did not substantially change linezolid exposure.

Conclusions:

• ABCB1 is identified as the primary transporter mediating the DDI between rifampin and linezolid.
• The DDI effect of high-dose rifampin on linezolid exposure is comparable to that of standard-dose rifampin.
• PBPK modeling provides a valuable tool for predicting transporter-mediated DDIs.