e10 Meeting abstracts

ZEBRAFISH AS A MODEL VERTEBRATE FOR CARDIOTOXICITY

Adrian Hill, Stephanie Albert, Bryony Richards, Jon Tinsley

VASTox plc, Abingdon, Oxfordshire, UK

Drug discovery is an increasingly expensive and risky process with high rates of safety related attrition often at late stages ofR&D. Withdrawals of drugs from the market, especially those affecting the cardiovascular system, demonstrate the difficulties ofpredicting safety pharmacology at pre-clinical stages. The zebrafish is a valuable in vivo model for expediting prioritisation ofcandidate drugs for development and flagging toxicity very early in the R&D process. Strong conservation of genetic pathways,increasing availability of disease models, its small size and ease of administration of compounds (micrograms) to the developingembryo, make zebrafish a very attractive, cost-saving vertebrate model for toxicity testing. VASTox plc has undertaken validation ofa cardiotoxicity assay using a set of thirty compounds targeting mechanisms known to affect the human heart (e.g. various ionchannel blockers; hERG blockers; adreno- and muscarinic receptor agonists and antagonists). Larval zebrafish were exposed at arange of doses via the water in 24-well plates for 0–3 h and assessed using a CCD digital camera. Rates of atrial (A) and ventricular(V) contraction were determined; thereby revealing any tachycardia, bradycardia and changes in the A:V ratio. The effects onzebrafish of known cardioactive compounds showed complete concordance to other higher order vertebrates. This included aspecific phenotype indicative for the detection of hERG blockers. These data suggest the zebrafish is a suitable model for assessingdrugs for toxicity at early stages of development.

doi:10.1016/j.vascn.2007.02.020

CHARACTERISATION OF TWO DIFFERENT ELECTROPHYSIOLOGICAL PATTERNS FOR DRUGS CAUSING TDP

Pascal Champeroux, Eric Martel, Sebastien Jude, Jean-Yves Le Guennec, Serge Richard

CERB, Baugy, France

45 reference compounds were tested on the model of isolated canine Purkinje fibres to determine whether drugs causing Torsadesde Pointes in Man could have a common electrophysiological pattern. Of them, 22 are clearly associated and/or labelled with a risk ofTdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The10 remaining drugs are without reports of TdP and QT prolongation. The relevance of different indicators such as APD90 increase,reverse use dependency, action potential triangulation or effect on Vmax was evaluated by comparison with available clinical data.Among drugs causing TdP, two subgroups of drugs corresponding to two different electrophysiological patterns were identified.These patterns were found only with drugs causing TdP. These results suggest that the propensity of a compound to cause TdP is linkedto common and particular electrophysiological properties in addition to hERG inhibition. Finally, a complex algorithm calledTDPscreenTM and based on two subalgorithms corresponding to the two particular electrophysiological patterns was defined.TDPscreenTM measures the degree of fitting with these two particular patterns and enables a rapid classification of any new drugcandidate between the three simply defined groups. This algorithm combined with our database should be very helpful for predictionof the risk of TdP in Man.

doi:10.1016/j.vascn.2007.02.021