Presentation Description: Drug-induced liver injury (DILI) can be enhanced by polypharmacy if co-administered drugs induce toxicity via mechanisms that have overlapping pathways. Resolution of DILI despite continued drug dosing, termed “adaptation”, is commonly observed in clinical trials, but the underlying mechanisms behind this phenomenon remain unclear. This talk will present how quantitative systems toxicology (QST) modeling can aid in evaluating potential drug-drug interactions (DDIs) at the hepatotoxicity mechanism level and exploring mechanisms underlying DILI adaptation. A case study will be presented where DILIsym, a QST modeling platform, was employed to assess potential DILI DDIs between metformin and solithromycin, both of which have been shown to induce modest mitochondrial dysfunction in vitro. QST modeling suggests that co-administration of metformin and solithromycin could lead to enhanced DILI, and adaptation through mitochondrial biogenesis could mitigate DILI responses.
Upon completion, participants will be able to understand drug-drug interactions (DDIs) at the hepatotoxicity mechanism level that may lead to enhanced drug-induced liver injury (DILI).
Upon completion, participants will be able to describe the application of quantitative systems toxicology (QST) modeling in prediction of DILI DDIs.
Upon completion, participants will be able to describe how QST modeling can be employed to assess mechanisms underlying adaptation to DILI.