Jean‐Pierre Valentin

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

The ICH S7A guideline defines safety pharmacology (SP) studies as those that investigate 'the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above', and permits both in vivo and in vitro techniques, as appropriate. The implementation of these ICH guidelines by the pharmaceutical industry--whilst providing a welcome and long overdue clarity into the scientific rationale, timing and regulatory requirements for SP studies--has also generated new challenges, both logistical and scientific, which have a major impact on drug development. These factors have motivated us to consider the introduction of in vitro techniques at an early stage of SP evaluation. Amongst these factors are: the expanded range of study types and physiological parameters to be assessed, the increased 'front-loading' of SP at earlier stages of the drug discovery process; the greater number of new chemical entities (NCEs) to be tested, together with limited compound supply; the condensed time frames for drug development, the higher and quicker throughput of in vitro vs. in vivo tests; the increasing predictability of in vitro tests and application of the '3Rs' rule of animal welfare (reduction, replacement and refinement). Also, there is the failure of traditional in vivo safety evaluation to predict certain clinical side-effects. The use of molecular (e.g. fluorescence and cloned ion channel), cellular (e.g. patch clamp and isolated cardiac cells) and tissue-based (e.g. microelectrodes and Purkinje fibres) methods offers a wide portfolio of novel techniques for SP evaluation of NCEs at a pre-in vivo stage. Thus, innovative in vitro techniques will contribute significantly to the early SP evaluation of NCEs.