The main role of preclinical pharmacokinetics and pharmacodynamics in drug discovery and development is to optimize candidate selection for the target therapeutic area, taking into consideration the type of agent required, and to predict the dose and dosing regimen for initial clinical trials with due concern to the requirements for effective treatment in the target therapeutic area. In order for this approach to be successful, a clear understanding is required for both the pharmacological target and drug disposition (absorption, clearance and distribution) of new chemical entities. A fundamental tenet in linking the pharmacokinetic and pharmacodynamic phases is that free drug in the systemic circulation is in equilibrium with the receptors. In the pharmacokinetic phase, only free drug can be cleared and drug is reversibly bound to tissues and blood. The pharmacodynamic phase is further subdivided into the interaction with the drug receptor triggering postreceptor events, eventually leading to actual drug effect. In this phase, only free drug can exert pharmacological effect and the free concentration of drug in plasma is in direct equilibrium with the interstitial fluid bathing most cells, since the capillary wall contains sufficient aqueous pores to allow the rapid passage of relatively small molecules, regardless of physicochemistry. Most receptor targets are accessed extracellularly. Therefore, one can expect that all drugs regardless of physicochemistry will be in direct equilibrium, at these targets, with free drug in plasma.
Key words: Bioavailability, Drug discovery, Formulations, PK-PD models, Sustained release dosage form.