Join us at SOT 2021
We are delighted to be attending SOT’s Virtual Annual Meeting and ToxExpo.
The Society of Toxicology (SOT) are dedicated to creating a safer and healthier world by advancing the science and increasing the impact of toxicology.
Head to our virtual exhibition booth
Come and discuss how our PhysioMimix OOC Microphysiological System can be incorporated into your drug discovery and development workflows to provide human-relevant insights into drug safety.
You can also catch us at two CN Bio hosted events
Exhibitor hosted session
How to be more predictive: Microphysiological Systems for humanized drug assessment. Dr. Tomasz Kostrzewski Director of Biology CN Bio and Piyush Bajaj Principal Scientist Sanofi
Our exhibitor hosted session
Presentation from Dr. Tomasz Kostrzewsk, CN Bio
Predicting drug toxicity remains a challenge due to limitations of standard pre-clinical models. Microphysiological Systems (MPS) can improve translatability of in vitro results by creating human-relevant, 3D cell culture models. We’ll discuss a pharma perspective on toxicological applications for single and multi-organ MPS, routes to wider adoption and regulatory acceptance.
Presentation from Piyush Bajaj, Sanofi
Drug induced liver injury is one of the most common safety related adverse events which leads to compound attrition within the drug discovery pipeline. In this talk, I will discuss how emerging in vitro liver platforms can be used within different stages of drug discovery to help screen the compounds, with a specific focus on the incorporation of liver specific clinical endpoints that can be measured within these advanced in vitro models which may help drive improved in vitro to in vivo translation of data.
Q&A Session | 20 Minutes
- What is an MPS & how does it compare to standard approaches?
- How to design single and multi-organ MPS experiments
- How to generate liver specific clinical endpoints
- How to improve in vitro to in vivo translation of data
- How MPS works alongside current approaches to improve regulatory submissions
Virtual poster presentation
With safety concerns being the major cause for failures in phases 1 and 2 of clinical trials, it is essential the need for more predictive models within drug discovery and development to improve translatability. In particular, standard in vitro models have several limitations that make testing chronic drug exposure highly challenging. In recent years focus has turned to human in vitro 3D liver models to provide the solution to these challenges. To understand causality and mechanistic aspects of drug-induced liver toxicity in detail, a human liver Microphysiological System (MPS) was used as in vitro model. Highly functional 3D liver microtissues were maintained under flow perfusion using the PhysioMimix™ MPS for up to 3 weeks. Using the MPS platform a broad spectrum of functional liver-specific endpoints were analysed (inc. clinical biomarkers), highlighting the MPS’ superiority to standard in vitro models. Acute (48 hrs) and chronic exposure (192 hrs) to two antidiabetic thiazolidinediones was investigated (troglitazone – known DILI caused by reactive metabolites) (pioglitazone – low DILI concern). Functional liver-specific endpoints were analysed from the culture medium (LDH, albumin, urea, ALT) and liver microtissues (ATP, CYP3A4), to create a distinct mechanistic “signature of hepatotoxicity”. Troglitazone caused acute, cMAX driven, toxicity that was detected by a number of endpoints (IC50LDH = 109.90 μM, IC50Urea = 69.09 μM and IC50Albumin = 94.46 μM). Using the cellular endpoints of ATP content and CYP450 activity, both acute and chronic toxicity was detected with similar IC50 values. Following exposure to pioglitazone some mild chronic toxicity was detected but again only for a subset of endpoints, demonstrating the important of understanding the full signature of hepatotoxicity.
Data was generated from independent studies conducted on the same primary human hepatocytes donor which demonstrated high levels of inter- and intra-study reproducibility. Overall demonstrate the liver MPS in vitro model is ideally suited to exploring the molecular mechanisms that underlie DILI and its association with hepatic toxicity. It will also be a highly useful tool for analysing the toxicity profiles of novel compounds and how they may behave in diverse patient subsets.
- How our liver MPS model can be used to assess drug-induced toxicity
- How our MPS platform brings uniqueness (clinical biomarkers can also be analysed)
- How it can help explore the molecular mechanisms that underlie DILI
- How it can be an extremely valuable tool in predicting hepatotoxicants