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Jan WillemJan Willem van der Laan is pharm/tox assessor for the Medicines Evaluation Board.

In pharmaceutical development, pharmacology and toxicology are often closely linked. While toxicology focuses on unwanted consequences of exposure and establishing a safe dose level defined by the NOAEL, pharmacology tends to focus on the mechanism/mode of action and the dose/effect-relationship of the intended action of the compound. Together they enable the application of a benefit/risk assessment, defining an acceptable level of adverse effects provided sufficient therapeutic advantage in treating a certain disease.

It is clear from certain classes of human pharmaceuticals that their pharmacology also governs their toxicity. In particular, biotechnology-derived proteins, often the human-like proteins, or close structural analogues, are known to show exaggerated pharmacological effects at high doses rather than unique off-target toxicity (Clarke et al, 2008). The specificity of these biopharmaceuticals allows a far more focused regulatory regime with respect to the recommended toxicological studies, and it would be challenging to further reduce the number of animals used.

The book Global Approach in Safety Testing describes recommended approaches to the non-clinical assessment of adverse effects, be they derived from off-target or exaggerated pharmacology. Of particular interest in the context of examination toxicity based on exaggerated pharmacological effects, the development of the regulations on biotech-derived proteins, as it took place the last 20 years in the framework of the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (commonly abbreviated as ICH) is thoroughly discussed (ICH Guideline S6). In an interesting turn in the development of small molecules, where off-target effects are more generally the focus, is a new focus on the role of pharmacology in the arcinogenicity of human pharmaceuticals. Although we have known for many years that pharmacological effects (stimulation of proliferative action) may be responsible for carcinogenic effects in animals, recent database analysis indicates that the pharmacological mode of action is the main cause for non-genotoxic carcinogenicity (except for stimulation of liver metabolism) in developed pharmaceuticals. This recognition has fostered an ongoing discussion of a reduction in carcinogenicity studies as screening tools, and has started a rather unique regulatory experiment (ICH S1 RND).