Accurately modeling complex drug-drug interactions (DDIs), including those involving non-CYP3A4 pathways, and underestimation of clearance predictions for substrates of aldehyde oxidase (AO) remain as challenges in drug development. In this webinar hosted in conjunction with ISSX, Diane Ramsden, Senior Director DMPK and Toxicology at Korro Bio, will present compelling data showcasing quantitative predictions of enzyme and transporter induction including a promising application involving accurate derivation of steady-state AUC changes stemming from complex DDIs including simultaneous induction and inhibition. 

Additionally, Stephanie Piekos, PhD, Principal Scientist, DMPK at Boehringer Ingelheim, will highlight data demonstrating improved intrinsic clearance predictions for compounds metabolized by AO, highlighting sustained, enhanced enzyme activity over extended culture periods as a new strategy for predicting AO-mediated metabolism. Together, these insights demonstrate how an advanced in vitro hepatic model can address distinct but complementary gaps in translational pharmacokinetics. 

Key Takeaways:

• Improved Induction Prediction Across Multiple Pathways: TruVivo demonstrated reproducible induction of key enzymes and transporters, including CYP2C8, CYP2C9, CYP2C19, UGT1A4, CYP3A4, and P-gp, offering broader DDI coverage than traditional hepatocyte monocultures, which often lack sensitivity outside the CYP3A pathway.
• Mechanistic Evaluation of Complex DDIs: The model effectively captured in situ interactions where compounds acted as both inducers and inhibitors. The net effect predictions closely aligned with clinical AUCR data, demonstrating translational value for assessing complex DDI scenarios when using clinically relevant concentrations.
• Quantitative Validation Against Clinical Outcomes: Induction parameters derived from the system enabled accurate in vitro to in vivo extrapolation (IVIVE), with the majority of predictions for CYPs, UGT1A4, and P-gp falling within accepted thresholds – supporting its utility for prospective DDI risk assessment.
• Improved Characterization of AO-Mediated Metabolism: Aldehyde oxidase, a key Phase I enzyme notoriously difficult to study in conventional in vitro or animal models, exhibited higher and more stable activity in TruVivo, enabling improved extrapolation to metabolism in humans.
• Accurate Clearance Predictions for Low-Turnover AO Substrates: For compounds where AO contributes substantially to metabolism, data generated in TruVivo resulted in hepatic clearance estimates within ~2-fold of clinical values, providing an improved method for early prediction of human pharmacokinetics for drugs exhibiting AO-mediated metabolism.

Guest Speakers: 

• Diane Ramsden, Senior Director DMPK and Toxicology, Korro Bio
• Stephanie Piekos, PhD, Principal Scientist, DMPK, Boehringer Ingelheim
• Edward LeCluyse, PhD, Research Fellow, LifeNet Health LifeSciences

ISSX Non-Member: $49 | Member: Free | Student: Free | Premier: Free  

View On-Demand Webinar: International Society for the Study of Xenobiotics: Quantifying Complex DDIs and Filling Gaps in AO-Mediated Clearance Predictions: Translational Applications of a Novel Hepatocyte Triculture System