Physiologically-based Simulation Modelling for the Reduction of Animal Use in the Discovery of Novel Pharmaceuticals

Abstract

The global pharmaceutical industry is estimated to use close to 20 million animals annually, in in vivo studies which apply the results of fundamental biomedical research to the discovery and development of novel pharmaceuticals, or to the application of existing pharmaceuticals to novel therapeutic indications. These applications of in vivo experimentation include: a) the use of animals as disease models against which the efficacy of therapeutics can be tested; b) the study of the toxicity of those therapeutics, before they are administered to humans for the first time; and c) the study of their pharmacokinetics —i.e. their distribution throughout, and elimination from, the body. In vivo pharmacokinetic (PK) studies are estimated to use several hundred thousand animals annually. The success of pharmaceutical research currently relies heavily on the ability to extrapolate from data obtained in such in vivo studies to predict therapeutic behaviour in humans. Physiologically-based modelling has the potential to reduce the number of in vivo animal studies that are performed by the pharmaceutical industry. In particular, the technique of physiologically-based pharmacokinetic (PBPK) modelling is sufficiently developed to serve as a replacement for many in vivo PK studies in animals during drug discovery. Extension of the technique to incorporate the prediction of in vivo therapeutic effects and/or toxicity is less well-developed, but has potential in the longer-term to effect a significant reduction in animal use, and also to lead to improvements in drug discovery via the increased rationalisation of lead optimisation.

Fish as Research Tools: Alternatives to In Vivo Experiments

“…As a consequence, up to 99% of all the animal tests are conducted on compounds that will not progress to the clinic, as they will be considered to be unsuitable for human use (128). The majority of the animal studies could be avoided by moving toward physiologically-based pharmacokinetic (PBPK) modelling (128,129). This is a mathematical modelling technique for predicting the absorption, distribution, metabolism and excretion of synthetic or natural, chemical substances in humans and other animal species.…”

The Use of Integrated and Intelligent Testing Strategies in the Prediction of Toxic Hazard and in Risk Assessment

“…Lipscomb et al 55 have described how PBPK models are developed, evaluated and applied in toxicity testing and health risk assessment, emphasising the importance of using a systems approach to provide much-needed improvements in understanding of the exposure-dose-response relationship. Thomas 56 assessed the challenge of using physiologically-based simulation modelling to reduce and replace the use of laboratory animal in the discovery of new pharmaceuticals.…”

Physiologically-based Pharmacokinetic Modelling for the Reduction of Animal Use in the Discovery of Novel Pharmaceuticals

“…However, as a result, even if a useful new drug emerges from the development pipeline, up to 99% of all animal studies will have been undertaken on compounds that will not progress to the clinic, because they will have been assessed as being unsuitable. To give an idea of the scale involved, the total number of animals used globally for in vivo studies each year is estimated at about 48-49 million, with pharmaceutical industry R&D accounting for up to approximately 17-million of these animals (1). If LI and LO account for 60-80% of this number (Figure 1), this corresponds to up to about 10-14 million animals.…”

“…This, in turn, can affect pharmacological activity, toxicity and elimination of the compound and/or its metabolites. Consequently, it can be argued that the majority of animal studies could be avoided, if the steps up to LI were more predictive of human health outcomes (1). Presented below, is a case, as part of this process, for moving away from animal studies and toward human-and physiologically-based pharmacokinetic (PBPK) modelling as a means of improving the selection of suitable drug candidates and, at the same time, avoiding certain animal studies.…”