Science Pool

Learn more about the advantages of human iPSC-derived cardiomyocytes including:

• Predictive and physiological cell model
• Applicable for drug development, preclinical research, and cardiac safety assessment
• Quantity, consistency and efficiency for HTS

Learn more about in Vitro iPSC research services at Evotec including:

• Robust differentiation protocols or adaptation of client protocols
• High-quality production of iPSC-derived cells at large scale
• Disease-relevant phenotypic read-outs for exploratory research and compound profiling/HTS
• Proprietary iPSC patent portfolio in tissue and disease modeling

Cardiotoxic drugs can display acute alteration in the mechanical function of the myocardium (functional changes) or morphological damage to cardiomyocytes and/or loss of viability (structural changes).   

In this poster, we focus on:

• the detection of functional cardiomyocyte changes through monitoring of calcium transients using human iPSC-derived cardiomyocytes
• the analysis of structural morphology using high content imaging (calcium homeostasis and mitochondrial function) as well as cellular ATP in human iPSC-derived cardiomyocytes
• the presentation of a strategy for understanding cardiotoxicity risk for novel compounds enabling in vitro to in vivo translation at an early stage in preclinical screening.

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Drug-induced mitochondrial dysfunction has been associated with organ toxicity and drug withdrawal. Highly specific and sensitive in vitro assays have been developed to predict mitochondrial dysfunction.

In this publication, we focus on:

• a background to mitochondrial toxicity
• a comparison of the Glu/Gal mitochondrial assay with the Seahorse assay for the prediction of mitochondrial toxicity
• how the Seahorse assay provides a mechanistic understanding of mitochondrial toxicity

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Drug-induced liver injury (DILI) is a leading cause of drug failure due to poor translation between traditional preclinical animal models and human clinical outcome. More sophisticated human in vitro cell-based models with multiparametric endpoints are now being developed to improve DILI prediction.

In this review article, we focus on:

• the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery
• how companies are addressing translational challenges using human relevant cell-based models
• a further insight into the key role of human exposure and hepatic drug uptake transporters (e.g., OATPs, OAT2)

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It is almost 50 years since MEA was first developed, however, the power of this technology in toxicology testing has only just been realised due to the introduction of the multi-well MEA allowing for its utility in high throughput
analysis.

In this whitepaper, we focus on:

• the current challenges within the pharmaceutical industry in terms of toxicology prediction
• how companies are addressing these challenges using human relevant cell-based models
• an in-depth evaluation of microelectrode array (MEA) and its key role in in vitro cardiotoxicity and neurotoxicity toxicology testing

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Our popular, easy-to-follow guide: 'Mechanisms of Drug-induced Toxicity' is available to read online.

Read about:

• an overview of the different mechanisms of toxicity including:
  
  • mitochondrial toxicity
  • reactive oxygen species (ROS) and oxidative stress
  • reactive metabolite formation
  • cell cycle mediated toxicity
  • apoptosis
  • genotoxic and non-genotoxic carcinogens
  • phospholipidosis
  • steatosis
  • cholestasis
  • cardiac ion channel effects and hypertrophy
• an assessment of the current in vitro methods available for determining mechanistic toxicology 
• key references and further reading related to the topic

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Fasiglifam (TAK-875) is a GPR40 agonist which was developed for the treatment of type 2 diabetes. However, during Phase III clinical trials, it was withdrawn due to adverse liver effects.

In this poster, we focus on:

• deciphering the mechanism of hepatotoxicity of fasiglifam (TAK-875)
• understanding the impact of plasma protein binding and mitochondrial effects by fasiglifam using the Seahorse flux analyser platform

Read our poster to learn more about our research!

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