title: A mechanistic, model-based approach to safety assessment in clinical development.
abstract: Assessing the safety of pharmacotherapies is a primary goal of clinical trials in drug development. The low frequency of relevant side effects, however, often poses a significant challenge for risk assessment. Methodologies allowing robust extrapolation of safety statistics based on preclinical data and information from clinical trials with limited numbers of patients are hence needed to further improve safety and efficacy in the drug development process. Here, we present a generic systems pharmacology approach integrating prior physiological and pharmacological knowledge, preclinical data, and clinical trial results, which allows predicting adverse event rates related to drug exposure. Possible fields of application involve high-risk populations, novel drug candidates, and different dosing scenarios. As an example, the approach is applied to simvastatin and pravastatin and the prediction of myopathy rates in a population with a genotype leading to a significantly increased myopathy risk.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e13; doi:10.1038/psp.2012.14; advance online publication 7 November 2012.
authors.affiliation: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Lippert
authors.forename: M
authors.initials: M
authors.lastname: Brosch
authors.forename: O
authors.initials: O
authors.lastname: von Kampen
authors.forename: M
authors.initials: M
authors.lastname: Meyer
authors.forename: H-U
authors.initials: HU
authors.lastname: Siegmund
authors.forename: C
authors.initials: C
authors.lastname: Schafmayer
authors.forename: T
authors.initials: T
authors.lastname: Becker
authors.forename: B
authors.initials: B
authors.lastname: Laffert
authors.forename: L
authors.initials: L
authors.lastname: Görlitz
authors.forename: S
authors.initials: S
authors.lastname: Schreiber
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: M
authors.initials: M
authors.lastname: Niemi
authors.forename: J
authors.initials: J
authors.lastname: Hampe
authors.forename: L
authors.initials: L
authors.lastname: Kuepfer