ADMET in Drug Development: What is the Role of Animals between In Silico : In vitro and In Vivo Humans?

Traditionally, experimental animal studies have constituted a backbone of drug development, in particular in toxicity evaluation. Almost from the beginning of modern drug development the reliance on animal experiments has been critisised on various grounds, from obvious differences between animals and humans to the emergence of 3R principles (refine, reduce, replace). Increasingly, in vitro methodologies have paved the way for more mechanistic and molecular approaches and, even more recently, the application of computational methods have provided platforms for simulating and integrating various approaches. Indeed, some circles even anticipate a more or less rapid disappearance of animal experiments (unless the question is about the animals’ own health and disease) or at least their replacement for a majority of current purposes by combined in vitro and in silico approaches. It is useful to remember some arguments related to this topic: 1. Variability is a fact of life at all levels of biological organization, be it a population or a gene. 2. Animals are different from humans and thus unreliable predictors without extensive focussed investigations (interspecies differences). 3. ’In vivo at an individual level’ constitutes such a complex whole that ’in vivo at a general (group, population etc) level’ could provide only approximate predictions (interindividual differences). 4. In vitro-methods can provide answers only to rather specific and well-understood and researched problems (in vitro-in vivo correlations). 5. in silico-tools, especially at a higher level of simulations and machine learning, have to be interpreted and explained in the end at the level of bioscience language and concepts (in this case pharmacology and toxicology). On the basis of the above arguments one might think that animal studies in drug development (as an example) are not very useful and the reason they are still a prominent part of DD has more to do with historical inertia than with a real necessity. Quite contrary, the use of experimental animals under proper ethical and scientific conditions offers still useful, sometimes absolutely necessary information for the advancement of drug development. In the following, some examples to illustrate this point are briefly described. Regulatory animal studies on toxicology and toxicokinetics constitute a general framework for understanding in vivo effects and behaviour of new chemical entities (NCE) including adverse effects in various bodily functions and organs and in the fate of a specific NCE in a whole organism. Currently the first kinetic study informs on mass balance, extent of absorption and elimination, metabolism, principal metabolites etc, all of which provide an initial view and comprehension of (toxico)kinetic characteristics of an NCE. This view is certainly of importance in the planning of future kinetic studies and in the interpretation of toxicity profile of an NCE. Currently in vitro studies in human-derived systems are run in conjunction with animal in vivo (and in vitro) studies and thus a comparison is possible, with obvious benefits. In regulatory toxicity studies it is of utmost importance to evaluate administered doses and also internal exposures (concentrations) of an NCE in relation to observed adverse effects, i.e. dose/concentration – response relationships, i.e. which doses/concentrations give rise to particular toxicities. It is not at all sure that similar toxicities at similar doses/concentrations would be expected when an NCE at a later stage (if ever) is given the first time into a human volunteer or patient. However, regulatory toxicity findings would constitute a background and starting point for more in-depth studies in vivo or in vitro, also employing human in vitro systems. It is quite possible that a particular PL-22 ADMET in Drug Development: What is the Role of Animals between In Silico – In vitro and In Vivo Humans?