Disease Models in Safety Pharmacology

The discipline of safety pharmacology can impact all stages of drug discovery and development from early target identification to regulatory approval. One of the key deliverables for safety pharmacology is the GLP studies to support Phase I clinical trials primarily in healthy volunteers but also in patients. The so-called core package of studies (investigating the adverse pharmacodynamic effects on the respiratory, cardiovascular, and central nervous systems) is well characterized and well served using normal healthy animals. Characterizing the phenotype of genetically modified animals may be useful to understand the hazards associated with a target modulation. Examples of when, and when not, the phenotype of knockout animals correlates with that observed with pharmacological agents in normal healthy animals and humans are given. For a number of years, some animal models of human disease (e.g., models of heart failure and cardiac arrhythmia) have been applied to safety pharmacology, and some show a different safety profile from that observed in normal healthy animals and as such may have the potential to increase the confidence in safety in the patient population. However, there are also examples where the translation of these models to humans has been far from perfect. Animal models of human disease have been used for decades in drug discovery, and similar translational challenges have been reviewed at length in the scientific literature. If we are to be successful in broadening the use of animal models of human disease in safety pharmacology, the learnings of many years of experience in drug discovery should be applied. Consideration must be given to both the internal and external validities of these models.