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A Combined Approach to Predicting Phospholipidosis using High Content Screening and In silico Modelling

Phospholipidsosis (PLD) is the excessive accumulation of intracellular phospholipids, which can ultimately lead to cellular toxicity. Lysosomotropism, or the accumulation of drugs in lysosomes is a known, direct mechanism of drug-induced PLD and a cause for concern in drug development. However, because drugs can also impact the synthesis and processing of phospholipids, drug-induced phospholipidosis can be an indirect risk presented by compounds that may not be lysosomotropic. While drug-induced phospholipidosis is a going concern in drug development, any direct links to outward manifestations of toxicological response in human subjects are not yet understood. There is clinical data, however, that correlates drug-induced PLD with potentially fatal risks of both organ-specific and systemic toxicities. Furthermore, drugs that cause PLD are likely to encounter costly delays in approval and time-to-market.

High Content Screening (HCS) is a useful tool in the detection of drug-induced phospholipidosis in a preclinical environment. By determining the accumulation of either drugs within lysosomes (by competitive loss of lysosomal dye uptake) or phospholipids within cells (by conjugation to dyes), HCS provides an insight into which drugs or compounds have the potential to cause PLD. In research performed by Cyprotex, published in Toxicology In Vitro, HCS methods were combined with simple in silico models to predict phospholipidosis potential in vivo. Using such an approach a sensitivity of 96%, a specificity of 92% and an overall accuracy of 94% was achieved compared to in vivo data. Therefore, adopting this combined in silico/in vitro strategy is highly predictive and enables compounds to be assessed at an early stage for this potential liability.

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