How much gets there and what does it do?: The need for better pharmacokinetic and pharmacodynamic endpoints in contemporary drug discovery and development.

Drug discovery is an expensive, slow and high risk enterprise. Only one in ten of the agents that enter clinical development is successful, with an average cost of US dollars 500-800 million and a typical time-scale of 10-15 years from preclinical discovery research to regulatory approval. On the other hand, many new targets are emerging from genome sequencing and the improved understanding of molecular pathology. Also, new technologies are increasing the speed and improving the efficiency of drug discovery. These new advances should facilitate progress towards the development of personalised therapies that are targeted to the genetics and molecular pathology of individual patients. The availability of pharmacokinetic (PK) and pharmacodynamic (PD) endpoints is absolutely critical to modern drug development. They allow us to understand how much of the drug gets there (into the body and ideally to the target cells) and what it does (with respect to modulation of the molecular target and the cognate biochemical pathways and downstream biological effects). PK and PD endpoints allow us to construct a pharmacological audit trail, so that all of the successive stages from drug administration through to biological effects and clinical outcome can be monitored and interpreted. This in turn provides a rational basis for decision making, e.g. stop/go, during development. An understanding of PK/PD relationships also gives us s basis for selecting the optimal drug dose and schedule. Better, less invasive methods are required. Developments in molecular/functional imaging show promise and current examples are provided.