2011 Annual Meeting of the Safety Pharmacology Society: an overview

Abstract

The keynote address of 2011 Annual Meeting of the Safety Pharmacology Society examined the known and the still to be known on drug-induced nephrotoxicity. The nominee of the Distinguished Service Award Lecture gave an account of his career achievements particularly on the domain of chronically instrumented animals for assessing cardiovascular safety. The value of Safety Pharmacology resides in the benefits delivered to Pharma organizations, regulators, payers and patients. Meticulous due diligence concerning compliance of Safety Pharmacology studies to best practices is an effective means to ensure that equally stringent safety criteria are applied to both in-licensed and in-house compounds. Innovative technologies of great potential for Safety Pharmacology presented at the meeting are organs on chips (lung, heart, intestine) displaying mechanical and biochemical features of native organs, electrical field potential (MEA) or impedance (xCELLigence Cardio) measurements in human induced pluripotent stem cell-derived cardiomyocytes for unveiling cardiac electrophysiological and mechanical liabilities, functional human airway epithelium (MucilAir^™) preparations with unique 1-year shelf-life for acute and chronic in vitro evaluation of drug efficacy and toxicity. Custom-designed in silico and in vitro assay platforms defining the receptorome space occupied by chemical entities facilitate, throughout the drug discovery phase, the selection of candidates with optimized safety profile on organ function. These approaches can now be complemented by advanced computational analysis allowing the identification of compounds with receptorome, or clinically adverse effect profiles, similar to those of the drug candidate under scrutiny for extending the safety assessment to potential liability targets not captured by classical approaches. Nonclinical data supporting safety can be quite reassuring for drugs with a discovered signal of risk. However, for marketing authorization this information should be complemented by a clear clinical proof of safety. The ongoing outsourcing process of Regulatory Safety Pharmacology activities from large Pharmas to contract research organizations should be taken as an opportunity to establish long-overdue in-house Exploratory Safety Pharmacology units fully dedicated to the optimization of clinical candidates on organ safety.

Keywords::

• animal model framework
• human iPSC-cardiomyocytes for cardiotoxicity
• MucilAir^™
• nephrotoxicity models
• organs on chip
• receptorome space definition, computational analysis, clinical safety studies essential for marketing authorization
• telemetry measurement of cardiovascular parameters
• value of Safety Pharmacology

Acknowledgements

The author would like to thank Mr H Holzegrefe for reviewing and greatly improving this text. Thanks are also extended to Prof D Ingber and W Pfaller as well as Drs S Boyer, K Bruse, S Constant, G Erdemil, L Ewart, L Guo, J Koerner, D Sarazan, P Siegl and R Wallis for their valued suggestions which helped the author to improve this report. Warm thanks are extended to S Boyer, S Constant, D Ingber, W Pfaller and Drs G Erdemil, L Ewart, L Guo, J Koerner, D Sarazan and R Wallis for generously providing their presentations and related published work for the preparation of the report. Additionally, the author would like to extend warm thanks, accompanied by heartfelt excuses, to HCM Boonen, L Buck, G Gintant, A Greiter-Wilke, RL Hamlin, JK Hennan, W Janssen, CS Kallesoe, A Laslop, D Leishman, N McMahon, D Park, G Ferber, J-P Valentin and KB Wallace who also generously provided their presentations which the author unfortunately could not summarize in this report due to space limitations. The author assumes full responsibility for the entire content of the report.