New Approaches to Drug Discovery

Jörg Lippert, Rolf Burghaus, Lars Kuepfer, Bart Ploeger, Stephan Schaller, Walter Schmitt, Stefan Willmann, Lippert, Jörg, Burghaus, Rolf, Kuepfer, Lars, Ploeger, Bart, Schaller, Stephan, Schmitt, Walter, Willmann, Stefan

The concept of a pharmacokinetics-pharmacodynamics (PK/PD) assessment of drug development candidates is well established in pharmaceutical research and development, and PK/PD modeling is common practice in all pharmaceutical companies. A recent analysis (Morgan et al., Drug Discov Today 17(9-10):419-424, 2012) revealed however that insufficient certainty in the integrity of the causal chain of fundamental pharmacological steps from drug dosing through systemic exposure, target tissue exposure, and engagement of molecular target to pharmacological response is still the major driver of failure in phase II of clinical drug development. Despite the rise of molecular biomarkers, ethical, scientific, and practical constraints very often still prevent a direct assessment of each necessary step ultimately leading to an intended drug effect or an unintended adverse reaction. Yet, incomplete investigation of the causality of drug responses is a major risk for translational assessments and the prediction of drug responses in different species or other populations. Mechanism-based modeling and simulation (M&S) offers a means to investigate complex physiological and pharmacological processes and to complement experimental data for non-accessible steps in the pharmacological causal chain. With the help of two examples, it is illustrated, what level of physiological detail, state-of-the-art models can represent, how predictive these models are and how mechanism-based approaches can be combined with empirical correlation-based concepts.