Projects

Project BA12 - Improved accuracy predictive toxicity measurements

Background

The UK is the 4th largest location for pharmaceutical R&D in the world. This success has been built on the back of a strong R&D pipeline, an excellent academic knowledge base, innovation from SMEs and outsourcing opportunities through CROs. Despite this, 75% of the cost of developing new pharmaceutical compounds (~£600m) can be attributed to failed drugs (Tufts Centre, 2008) which were not identified by cell assays during preclinical screening.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) estimates that the probability of a drug reaching market following pre-clinical studies is around 1%, with the main causes of failure being lack of efficacy (25%), high toxicity (20%) and low safety (12%). Current (2D) cell models do not accurately predict these causes of drug failure. Placing cells in a more realistic in vivo-like (3D) environment can be used to overcome some of these limitations.

However, these systems are hindered by a lack of reference methods that can be translated across a range of cell platforms to link cell quality with toxicological endpoints, closing the gap to in vivo models and improving the robustness of cell assays.

This project aims to improve the accuracy of cell-based toxicity screens by identifying the cell quality parameters which reduce the robustness of in vitro toxicity assays and by developing reference methods to increase data comparability. This project will establish the measurement infrastructure for 3D cell-based toxicity testing, increasing the reproducibility of in vitro measurement and supporting the development of next generation in vitro assays.

This project will impact economically via reduced drug development costs through increased measurement reproducibility and better data comparability leading to reduced failure rates. Follow-on quality of life impact will be felt through more efficient drug development and reduced time to market.

Aims and Objectives

This project aims to develop a portfolio of measurement tools which can be applied in combination to relate cell quality with functional properties and predict toxicity of a compound. This measurement portfolio will be used to generate reference methods applicable to cells grown in standard culture and complex 3D environments. This will allow the development of reference standards which can be used to increase the accuracy of toxicity measurements.

• To examine the suitability and accuracy of techniques to measure the viability, morphology and stress status of primary hepatocytes grown in standard cell culture and in 3D culture platforms.

• To examine the accuracy of techniques to measure cytochrome-P450 activity developed under the CBM project DD3. The challenge will be in ensuring the accuracy of these techniques when applied to cells maintained in 3D culture.

• To examine how measurements developed throughout the project can be used to link cell quality characteristics with toxicity measurements using reference compounds with known toxicity profiles.

• To develop reference methods in liaison with European organisations such as ECVAM and/or international metrology links through CCQM.