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European Pharmaceutical Contractor

Vitro Preclinical Lead Optimisation Technologies (PLOTs) in Pharmaceutical Development

Sensible lead candidate selection for preclinical drug development and registration should reduce the high rate of attrition, the cost of which increases with the distance that the failed candidate has proceeded down the R&D pipeline. Rates of attrition are especially high during the early regulatory preclinical toxicology and clinical phases of testing. Not surprisingly, because of the large number of hits identified from primary high throughput discovery screens, lead candidate identification has emerged as a critical decision-making milestone. In short, there is a need for early, rapid and robust preclinical lead optimisation technology (PLOT) screening assays which will allow a lead series of compounds to be ranked for desirable or undesirable characteristics.

These PLOTs (1) must be sufficiently rapid to interface with high throughput discovery screens without creating a further bottleneck, be predictive of drug failure and be cost-effective (see Figure 1). The assays which constitute the PLOT platform are typically in vitro systems, miniaturised and amenable to automation, thereby achieving the required throughput with minimal compound use - another crucial factor for facilitating the process of lead optimisation (see Figure 2). Industry recognition of the '3 Rs' (Reduction, Refinement and Replacement) through the implementation of the ethical review process (ERP), has been instrumental in the increasing acceptance and incorporation of alternative in vitro models, especially in early drug development projects.


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By Professor Chris Atterwill, Director of the Biosciences Division at Huntingdon Life Sciences

Professor Chris Atterwill trained as a Pharmacist at the University of London and gained a PhD in Pharmacology. Having completed three postdoctoral positions with the MRC and the University of Oxford, he took up a position as Head of In Vitro Toxicology at SmithKline and French and subsequently gained his FRCPath and FRPharmS through his work in promoting and developing animal alternative technologies in toxicology.

He then moved to the position of Chair in Biosciences at the University of Hertfordshire and later became Head of Preclinical Drug Safety at Roche Discovery UK. He joined Huntingdon Life Sciences in 1999 where he is the Director of the Biosciences Division. He also serves on the UK Government Home Office Animal Procedures Committee (APC).

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Professor Chris Atterwill
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