title: Modeling and Simulation of In Vivo Drug Effects.
abstract: 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.
authors.affiliation: Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany. joerg.lippert@bayer.com.
authors.forename: Jörg
authors.initials: J
authors.lastname: Lippert
authors.affiliation: Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Burghaus
authors.affiliation: Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kuepfer
authors.affiliation: Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany.
authors.forename: Bart
authors.initials: B
authors.lastname: Ploeger
authors.affiliation: Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schaller
authors.affiliation: Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Schmitt
authors.affiliation: Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Willmann
mesh_terms: D000818:Animals; D003198:Computer Simulation; D055808:Drug Discovery; D006801:Humans; D008954:Models, Biological; D000069437:Pharmacological Phenomena; D049490:Systems Biology
keywords: Mechanism based; PK/PD; Systems biology; Systems pharmacology; Translational