Science Pool

LC-MS provides the analytical endpoint for most discovery ADME assays. There is a constant drive to reduce LC-MS run times whilst maintaining quality. 

In this presentation, we focus on:

• a comparison of triple quadrupole MS/MS vs TripleTOF MS
• validation data for performance of the TripleTOF MS 
• use of the TripleTOF in high throughput ADME screening including intrinsic clearance assays and soft spot analysis.

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Due to an aging population, polypharmacy is increasing. Drug-drug interactions account for 5% of UK hospital admissions, and are a particular concern for common co-meds such as statins.

In this presentation, we focus on:

• a background to drug-drug interactions (DDI)
• the use of the mechanistic static models in the prediction of transporter-mediated DDI
• a comparison of the different published models and their performance 

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Pilocarpine is a muscarinic cholinergic agonist which is used as an epilepsy model in rats. 

In this presentation, we evaluate:

• the seizurogenic response of pilocarpine in vitro in different neuronal models including rat cortical neurons, rat hippocampal neurons and a human iPSC-derived co-culture model
• the importance of maturation of the cells (DIV)
• the use of MEA for the sensitive detection of firing, bursting and synchrony of the cells

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Human-derived 3D cell-based models are more representative of in vivo cellular physiology and have improved longevity in vitro.  

In this presentation, we focus on:

• causes of drug failure in drug development
• the advances in high content screening
• developments in 3D cell-based models including organ-specific cellular models
• the prediction of tissue specific toxicities such as hepatotoxicity (DILI), cardiotoxicity, nephrotoxicity and neurotoxicity

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Mitobiogenesis (or mitochondrial biogenesis) is defined as the growth and division of pre-existing mitochondria. Drug-induced perturbations in this process can result in mitochondrial dysfunction or toxicity. 

In this presentation, we focus on:

• mechanisms involved in mitochondrial toxicity including drug-induced mitobiogenesis
• the development of a high throughput high content imaging assay for detecting drug-induced effects on mitobiogenesis
• validation of the assay using known drugs which inhibit mitochondrial DNA and protein synthesis (e.g., antibiotics, anti-viral and anticancer drugs) as well as some non-mitochondrial toxicants.

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The brain is a complex organ. Find out more about the use of in vitro 3D co-culture brain microtissues for predicting human CNS liability.

In this presentation, we focus on:

• a background to drug-induced brain neurotoxicity
• the importance of astrocytes and their function
• the use of brain 3D co-cultured microtissues
• neurotransmitter pathway development over time
• high content screening (HCS) of brain microtissues and validation data

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Cardiotoxicity is a key cause of late stage attrition in drug development. iPSC-derived cardiomyocytes remain viable for more than 2 weeks on MEA plates. As MEA measures electrical activity without addition of any reagents, the cells can be exposed and monitored over extended time periods.

In this presentation, we focus on:

• a background to MEA
• design of the assay for detecting cardiotoxicity following chronic exposure to drugs
• case studies for cardiotoxic drugs with different mechanisms (hERG traffickers, multichannel blockers, specific ion channel effects)

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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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