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toSAA, ALAT and CK showed a high inter-individual variability andwere thus poorly indicative of cardiac toxicity. ASAT activity wasincreased, but this enzyme is not specific to cardiac tissue.

doi:10.1016/j.toxlet.2009.06.765

Abstracts / Toxicology L

21he European IMI SAFE-T Consortium: Qualification of transla-

ional safety biomarkers�

rank Dieterle 1,∗, Ina Schuppe-Koistinen 2, Neus Prats 3, Laurenrown 4, Patrice Cacoub 5, Thierry Poynard 5, Joe Keenan 6,homas Krahn 7, Arno Kalkuhl 8, Ulf Neumann 9, Teresa Padro 10,homas Joos 11, Karin Briner 12, Jean-Marc Vidal 13, Johnasselden 14, Huesseyin Firat 15, Landry Cochard 16, Nicolechneierhahn 17, Denise Robinson-Gravatt 18, Lucetteoesegger 19, Nadir Arber 20

Novatis, Translational Sciences, Basel, Switzerland, 2 AstraZeneca,weden, Sweden, 3 Almirall, Barcelona, Spain, 4 Amgen, Brussels,elgium, 5 AP-HP, Paris, France, 6 Argutus, Dublin, Ireland, 7 Bayerchering, Wuppertal, Germany, 8 Boehringer-Ingelheim, Biberach,ermany, 9 Charite, Berlin, Germany, 10 CSIC-ICCC, Barcelona, Spain,

1 EDI-RBM, Reutlingen, Germany, 12 Eli Lilly, Hampshire, Unitedingdom, 13 EMEA, London, United Kingdom, 14 GSK, Brentford,nited Kingdom, 15 Firalis, Huingue, France, 16 InterfacEurope,russels, Belgium, 17 NMI, Reutlingen, Germany, 18 Pfizer, Sandwich,nited Kingdom, 19 Roche, Basel, Switzerland, 20 SMC Tel-Aviv, Telviv, Israel

lack of specific and sensitive mechanistic safety markers andheir respective assays for human samples is regularly delayingrug development programs. This is especially the case when aisto-pathological signal is seen in preclinical toxicology studieshich cannot be adequately monitored in humans. For example,

urrent standards to monitor the safety of the kidney (Serum Cre-tinine, BUN) are late and insensitive and can only be increasedhen 50–60% of the kidney function is lost. In the case of liver

afety, current standards (AST, ALT, Bilirubin) are not specific and doot predict who will recover and who will develop fulminant liverisease. Furthermore, currently no accepted clinical safety markersre available to detect and monitor drug-induced vascular injury inuman.

The SAFE-T Consortium (Safer and Faster Evidence-based Trans-ation), which is part of the Innovative Medicine Initiative (IMI),

hich is composed of 10 pharma companies, six academic centersf excellence, four SMEs and the European Medicine Agency, willstablish a scientific biomarker qualification strategy and apply itn clinical biomarker studies for the translation, performance test-ng and eventual regulatory qualification of safety biomarkers forrug-induced kidney, liver and vascular injury (DIKI, DILI and DIVI).

In this presentation, the background of this consortium, thebjectives, strategies and different steps and milestones are pre-ented such as:

Definition of scientific clinical qualification processes for safetybiomarker qualification in clinical development with healthauthorities.Characterization of the needs for new clinical biomarkers com-pared to current standards and criteria to be met in all three organareas (pathologies).Assay development procedures: fit for purpose for exploratoryphase, multiplexed and GLP-validated for confirmatory phase.Establishing baseline values and their variability in healthy sub-jects and various patient populations.

Defining and running protocols to measure the performance ofthese biomarkers against current standards in clinical studiesand hospital units with expected drug-induced injuries and inpatients with relevant diseases (exploratory and confirmatoryphase for all three organs).

189S (2009) S57–S273 S157

Setting up a common database and biosample repository to beable to build up on any new data set upcoming in the future andto investigate further upcoming biomarker candidates.Qualification of appropriate markers for regulatory decision mak-ing in clinical contexts together with heath authorities.Gaining mechanistic understanding when needed via pre-clinicalstudies.

It is expected that this consortium will strongly influence thecience and the regulatory acceptance of safety biomarker to sup-ort drug development and ultimately to improve patients’ healthnd safety.

Selected for Oral Presentation.

oi:10.1016/j.toxlet.2009.06.764

22ardiac biomarker evaluation following Isoprenaline adminis-ration in the minipig

écilia Gerhardy ∗, Anne Reiniche, Olivier Boucheix, Jean-Paulriffaux, Hélène Voute

MDS, Drug Safety Assessment, L’Arbresle, France

he objective of the study was to investigate the pertinence of var-ous biomarkers of cardiac toxicity in the minipig.

Four Göttigen 10-month-old male minipigs were used. A Millaratheter pressure transducer was inserted into the left ventricleia the left carotid artery of each minipig. The left jugular veinas catheterised with a polyethylene 6F catheter for blood sam-ling. The minipigs were maintained under general anaesthesiaith isoflurane in oxygen throughout the experiment.

All minipigs were given Isoprenaline hydrochloride. The firstnimal received 0.5 mg/kg as an intravenous bolus injection. Twonimals received 6 mg/kg infused intravenously over 1 h. Theemaining animals received 0.5 mg/kg by the subcutaneous route.

The left ventricular pressure and electrocardiogram (lead IIerivation) were continuously recorded using Notocord-hem v.3.4oftware. Blood samples were taken before dosing and at vari-us time-points up to 150 min after dosing and used for clinicalhemistry determinations. The parameters evaluated includedroponin I, serum amyloid A (SAA), aspartate aminotransferaseASAT), alanine aminotransferase (ALAT) and creatine kinase (CK).histopathological examination of the heart was performed for all

nimals.The serum levels of troponin I increased following administra-

ion of Isoprenaline and were closely correlated with the degreef cardiac injury indicated in the ECG and histopathology findings.