An EU perspective on the use of in vitro methods in regulatory pharmaceutical toxicology.

Some in vitro methods such as those used in the assessment of genotoxicity, receptor-binding and QT-prolongation are well established in regulatory pharmaceutical toxicology. In vitro systems to study metabolic profiles, P450 isoforms, drug interactions, etc. or to provide metabolic activation in genotoxicity assays are extremely useful, but are subject to a number of important limitations. In vitro models are also employed on an ad-hoc basis for other purposes, for example, to help investigate mechanisms underlying in vivo findings. At the current stage of technical development of alternative methods, rapid replacement of the pivotal animal studies used in drug safety assessment seems unlikely. The existing in vivo models have good predictive ability regarding toxic effects in humans, are underpinned by an extensive literature and form the basis of most regulatory toxicology guidelines. Integrated in vitro testing strategies, meant to replace conventional repeated-dose studies, are still relatively undeveloped. Emerging technologies such as transgenics, toxicogenomics and toxicoproteomics, although they rely on the continued use of animals, have considerable potential in terms of reduction and refinement of in vivo methods.