Science Pool

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 However, during Phase III clinical trials, it was withdrawn due to adverse liver effects.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

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Pharmacokinetic/pharmacodynamic (PK/PD) modelling plays an important role in drug development, especially in the case of antibiotics where the data generated is used for dose prediction up to Phase 2 clinical trials. This enables efficient study designs and identification of optimal dosing regimens that may suppress drug resistance.  

In this poster, we focus on:

• mathematical modelling of in vivo and in vitro data to generate a rational design with reduced animal requirements in order to determine the pharmacodynamic driver and magnitude of antibiotic efficacy
• optimisation of the clinical dose regimen in Phase 2 clinical trials

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Vanoxerine is a multi-ion channel blocker. For this reason, it was developed as a therapy for atrial fibrillation. However, in Phase III trials, 11.5% of patients developed torsades de pointes. Using MEA and human iPSC-derived cardiomyocytes, it was possible to detect this cardiotoxic liability. 

In this poster, we focus on:

• the use of MEA and human iPSC-derived cardiomyocytes to detect vanoxerine arrhythmias
• the time dependent effect of vanoxerine cardiotoxicity
• the ADME properties of vanoxerine which may impact on its cardiotoxic effect

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Reducing the sample cycle time for LC-MS analysis is critical in increasing throughput and improving efficiency.

In this poster, we focus on:

• the development of a ultra-fast chromatography method with rapid cycle time
• the analysis of the sensitivity, linearity, reproducibility, robustness and matrix effects for the method
• applicability to intrinsic clearance determination

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TAK-875 (fasiglifam) is a GPR40 agonist which was developed for the treatment of type 2 diabetes. However, TAK-875 was withdrawn from phase III clinical trials due to drug-induced liver injury (DILI).

In this poster, we focus on:

• investigating the mechanism behind the hepatotoxicity of TAK-875
• an in-depth understanding of the effect of TAK-875 on mitochondrial toxicity 
• understanding the impact of plasma protein binding

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In order to accurately predict human pharmacokinetics and efficacious dose, a robust measurements of clearance is essential.

In this poster, we focus on:

• a novel primary human hepatocyte media supplement (HepExtend^TM)
• a comparison of HepExtend^TM with the widely used CM4000 with and without a Geltrex overlay
• a correlation of scaled in vitro human intrinsic clearance with in vivo human intrinsic clearance

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Advances in human iPSC-derived neuronal models in conjunction with microelectrode array (MEA) technology has enhanced our understanding of complex burst organisation and network characteristics in humans. This now provides a viable human model for studying drug-induced toxicity and CNS liabilities as well as potential pharmacology effects on the neurones.

In this poster, we focus on:

• investigating co-cultures of human iPSC-derived glutamatergic neurons with astrocytes on the MEA platform
• determining spike activity, burst organisation and network organisation (synchrony) patterns for different types of CNS compounds (GABA_A agonists, potassium channel blockers, opioid receptor agonist, glycine receptor antagonist and cholinergic and muscarinic receptor agonists)
• understanding developmental and pharmacological responses when assessed by MEA

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Drug or chemical-induced nephrotoxicity is responsible for 25% of renal failure in the clinic.

In this poster, we focus on:

• a comparison of 2D and 3D human primary kidney cell-based models for predicting nephrotoxicity
• the use of mono and co-culture kidney models
• using HCS for the simultaneous detection of DNA structure, GSH content, mitochondrial toxicity and phospholipidosis

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Pilocarpine is a muscarinic receptor agonist which is used as a model inducer of epilepsy in the rat. We evaluated the seizurogenic response of pilocarpine using an in vitro MEA platform.

In this poster, we focus on:

• a comparison of pilocarpine response in different neuronal cell types; cryopreserved rat cortical neurons, cryopreserved rat hippocampal neurons and a co-culture of human iPSC-derived glutamatergic neurons with astrocytes
• the impact of DIV and cell maturation on the response
• identifying muscarinic receptor expression over time

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The benefits of 3D cell-based models in the prediction of drug-induced liver injury are now being realised. 

In this poster, we focus on:

• the use of 3D models (cryopreserved human hepatocytes co-cultured with human non-parenchymal cells compared with HepaRG monocultures)
• cytochrome P450 (CYP) activity in the different models
• HCS analysis of DNA structure, GSH content, ROS formation and mitochondrial function
• prediction of DILI potential for a set of DILI-positive and negative compounds

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