I attended one of the advanced Continuing Education (CE) courses offered during the SOT 62nd Annual Meeting and ToxExpo in Nashville, Tennessee. The course, “In Vitro to In Vivo Extrapolation Strategy and Guidance across Organ System Toxicities,” was chaired by Samantha Faber, Takeda Development Center Americas Inc., and Helena Hogberg-Durdock, NIEHS. The course provided an update on current in vitro to in vivo extrapolation strategies used in various research sectors for regulatory considerations.
In ongoing and emerging wave of rationally designed nonanimal research methods (NAMs) and promoting the 3Rs (replace, reduce, and refine the use of animals in research), in vitro to in vivo extrapolation is broadly considered a prerequisite bridge in translating in vitro findings to in vivo. Despite significant advancements, there are still gaps and limited understanding of NAMs validation and adoption of in vitro–in vivo extrapolation (IVIVE) strategies in regulatory frameworks. Therefore, to address these gaps and foster a discussion on IVIVE paradigms, this CE course explored IVIVE strategies and approaches critical to the regulatory framework.
Dr. Faber welcomed everyone to the course and turned the session to Jingjie Zhang who focused on IVIVE strategies in the field of inhalation toxicity in tobacco-free nicotine products, ADME tools to approximate toxicity, and the role of various absorption barriers (GIT, BBB) in toxicity studies. Dr. Zhang emphasized how dose and exposure are often used interchangeably, but exposure does not equal biologically relevant dose. Animal models and nonanimal models, such as in vitro models and computer modeling, are exciting research tools, but in understanding complex disease physiology, these models lack integration of all variables and, therefore, necessitate the inclusion of human-relevant research models. To develop more valuable insights in the field of toxicity, the best approach lies in collaborative efforts, working together to integrate in vitro, in vivo, and ’omics datasets to fully develop an understanding of organ toxicities.
Dr. Zhang was followed by Zhichao Liu, who talked about the use of toxicogenomic and physiologically based pharmacokinetic (PBPK) modeling to elucidate various aspects of drug-induced liver injury. Dr. Liu introduced the audience to US Food and Drug Administration (US FDA) Drug Modernization Act 2021 and broadened the scope of acceptable preclinical models for drug development and humane alternatives to drug toxicity testing. He emphasized that studies examining organ toxicities must use relevant exposures both in terms of composition and concentrations of toxicants. Also, it is important to consider what therapeutic molecules are being extrapolating when extrapolating between various toxicogenomic assays.
Dr. Hogberg-Durdock was next in line and focused on an integrated approach to assess developmental neurotoxicity. Dr. Hogberg-Durdock introduced the audience to the concept of learning from existing animal data using artificial intelligence (AI) tools. One such AI-based package is AnimalGAN, which is responsible for generating specific animal study datasets for new and untested chemicals by learning from legacy animal study data. The revolution has begun, and over the next few years, we’ll see tremendous progress in learning from existing animal data with AI tools.
The fourth speaker was Vicencia Toledo Sales. Dr. Toledo Sales offered the audience a very balanced point of view regarding cardiovascular NAMs and available 2D and 3D cardiac toxicity models. The presentation was focused on unraveling uncertainty in PBPK and IVIVE modeling, and how harmonization on protocols and transferability of assays will likely overcome this barrier.
The final speaker Jean-Lou Dorne focused on strategies and guidance for the implementation of IVIVE approaches in chemical risk assessment. Dr. Dorne shed light on regulatory considerations and future directions toward the adoption of the IVIVE approach in the field of toxicology.
Overall, the course was very informative and highlighted the complexity of extrapolating in vitro–in vivo data to study the safety, toxic potential, and potential mechanisms of drugs. The concept of developing human relevant models and learning from existing animal data using tools of artificial intelligence were my key takeaways from this course.
This blog reports on the Continuing Education course titled “In Vitro to In Vivo Extrapolation Strategy and Guidance across Organ System Toxicities” that was held during the 2023 SOT Annual Meeting and ToxExpo. All 2023 Continuing Education courses were recorded and are available for virtual viewing through the SOT CEd-Tox online library. SOT Postdocs and Students and individuals from select countries receive free access to all CE courses.
This blog was prepared by an SOT Reporter and represents the views of the author. SOT Reporters are SOT members who volunteer to write about sessions and events in which they participate during the SOT Annual Meeting and ToxExpo. SOT does not propose or endorse any position by posting this article. If you are interested in participating in the SOT Reporter program in the future, please email SOT Headquarters.