Combining transporter data with quantitative systems toxicology modeling (DILIsym) to impact decisions in drug development

Date: December 07 2016
Presenter(s): Dr. Brett Howell, Dr. Kyunghee Yang

You can download the presentation slides here!

The Webinar was presented on 7 December, 2016 by Dr. Brett Howell, Chief Executive Officer at DILIsym Services, Inc. and Dr. Kyunghee Yang, Scientist at DILIsym Services Inc., US.

Summary: A quantitative systems toxicology (QST) model of drug-induced liver injury (DILI) has been developed through the DILI-sim Initiative over the past 7 years to assist in the safety characterization of compounds in clinical development. The emerging platform, DILIsym®, is capable of predicting and explaining hepatotoxicity due to bile acid transporter inhibition, mitochondrial dysfunction, oxidative stress, and lipotoxicity. DILIsym includes interacting sub-models such as: a PBPK sub-model of drug disposition; a bile acid representation of homeostasis and disruption by transporter inhibition; a mitochondrial function and dysfunction sub-model including lipid metabolism and lipotoxicity; a sub-model of oxidative stress generation and clearance; a cell death representation of hepatocyte apoptosis, necrosis, and regeneration; and representations of many well-accepted and novel biomarkers of liver injury. Key questions addressable with the software include how in vitro toxicity assay results translate to in vivo scenarios, the relevance of pre-clinical results for humans, what mechanisms could be responsible for observed DILI biomarkers, and how biomarker results translate to patient safety. Case studies will be presented demonstrating how drug metabolism and disposition intersect with hepatotoxicity, and how utilizing mechanistic modeling approaches incorporating this information allows for a better understanding of safety risks. Key areas of focus will include predicting effects of bile acid transporter inhibition on liver safety and the use of modeling and simulation methods to provide context for biomarker signatures that are difficult to interpret.

Presenters: BRETT A HOWELL, PH.D. Chief Executive Officer, DILIsym Services, Inc. Associate Director, DILI-sim Initiative

Brett

Brett A Howell, Ph.D., is the chief executive officer of DILIsym Services, Inc., a company developing and using DILIsym® software to improve the development of safer drug therapies, and has served on the Board of Directors of the company since 2016. He is also an associate director of the DILI-sim Initiative since 2011. In addition to being involved in operations, training and software architecture, Dr. Howell contributes technically in the areas of PBPK modeling, immune response, consulting project leadership and biomarkers. Dr. Howell has published over 20 scientific papers in the areas of PBPK/PD modeling, in vitro toxicity testing, novel drug delivery systems, and drug safety. He has given invited scientific presentations at numerous national and international meetings, including the Society of Toxicology annual meeting, the Japanese Society of Toxicology annual meeting, the annual FDA/AASLD Drug-Induced Liver Injury meeting, the American Conference on Pharmacometrics (ACOP) annual meeting, the European Microsomes and Drug Oxidations annual meeting, and the Drug Information Association (DIA) annual safety meeting. He serves on the editorial board for the prominent Quantitative Systems Pharmacology (QSP) journal, “CPT: Pharmacometrics & Systems Pharmacology,” published by the American Society for Clinical Pharmacology and Therapeutics. Prior to joining DILIsym Services, Dr. Howell was a research investigator and research scientist at The Hamner Institutes for Health Sciences, a non-profit organization that focused on translational biomedical research. He holds a Ph.D. in chemical engineering from the University of Florida and Bachelor of Science degrees in chemical engineering and textile engineering from North Carolina State University.

KYUNGHEE YANG, PH.D. Scientist, DILIsym Services, Inc. Developer, DILI-sim Initiative

Yang

Kyunghee Yang, Ph.D., is a scientist for DILIsym Services, Inc. and software developer working on the DILI-sim Initiative modeling team. Dr. Yang’s research focuses on the computational modeling of drug-induced liver injury (DILI) regarding interference of bile acid transport by hepatotoxic drugs Dr. Yang received her B.S. in pharmacy and M.S. in pharmacokinetics from Seoul National University, South Korea, and Ph.D. in Pharmaceutical Sciences from University of North Carolina at Chapel Hill. Her graduate research focused on defining the mechanisms of DILI involving the interactions in efflux of bile acids and drugs. As a result of her research, she earned numerous fellowship awards. Dr. Yang has published scientific papers in the areas of drug metabolism and transport, regulation of drug metabolizing enzymes during pregnancy, and systems pharmacology modeling of DILI. She has been invited to speak at multiple scientific meetings including the FDA DILI Conference and ASCPT Annual Meeting. She has worked closely with the DILIsym modeling team since 2011 and joined the team in 2014.