The European IMI SAFE-T Consortium: Qualification of translational safety biomarkers

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  • Abstracts / Toxicology Letters 189S (2009) S57S273 S157

    Y21The European IMI SAFE-T Consortium: Qualication of transla-

    tional safet

    Frank DieteBrown4, PaThomas KraThomas JooHasselden1

    SchneierhahDoesegger1

    1 Novatis, TrSweden, SwBelgium, 5 ASchering, WGermany, 911 EDI-RBM,Kingdom, 13

    United KingBrussels, BelUnited KingAviv, Israel

    A lack of stheir respedrug develohisto-pathowhich canncurrent stanatinine, BUwhen 506safety, currenot predictdisease. Furare availablhuman.

    The SAFElation), whwhich is coof excellencestablish ain clinical bing and evedrug-induc

    In this pobjectives,sented such

    Denitionbiomarkeauthoritie

    Characterpared to careas (pat

    Assay devphase, mu

    Establishijects and

    Deningthese bioand hosppatients wphase for

    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.

    ication of appropriatemarkers for regulatory decisionmak-clinical contexts together with heath authorities.

    ingmechanistic understandingwhenneeded via pre-clinicales.

    expected that this consortium will strongly inuence theand the regulatory acceptance of safety biomarker to sup-

    ug development and ultimately to improve patients healthfety.

    cted

    1016

    c bioin t

    Gerhx, H

    rug S

    jectivomarr Gtr prleft

    theteTheourminireces reing aleft

    ion)re. Be-ptryin I,, alanpaths.seruIsopiac inLAThus ped, b

    1016y biomarkers

    rle1,, Ina Schuppe-Koistinen2, Neus Prats3, Laurentrice Cacoub5, Thierry Poynard5, Joe Keenan6,hn7, Arno Kalkuhl8, Ulf Neumann9, Teresa Padro10,s11, Karin Briner12, Jean-Marc Vidal13, John4, Huesseyin Firat15, Landry Cochard16, Nicolen17, Denise Robinson-Gravatt18, Lucette

    9, Nadir Arber20

    anslational Sciences, Basel, Switzerland, 2 AstraZeneca,eden, 3 Almirall, Barcelona, Spain, 4 Amgen, Brussels,P-HP, Paris, France, 6 Argutus, Dublin, Ireland, 7 Bayeruppertal, Germany, 8 Boehringer-Ingelheim, Biberach,Charite, Berlin, Germany, 10 CSIC-ICCC, Barcelona, Spain,Reutlingen, Germany, 12 Eli Lilly, Hampshire, UnitedEMEA, London, United Kingdom, 14 GSK, Brentford,dom, 15 Firalis, Huingue, France, 16 InterfacEurope,gium, 17 NMI, Reutlingen, Germany, 18 Pzer, Sandwich,dom, 19 Roche, Basel, Switzerland, 20 SMC Tel-Aviv, Tel

    pecic and sensitive mechanistic safety markers andctive assays for human samples is regularly delayingpment programs. This is especially the case when alogical signal is seen in preclinical toxicology studiesot be adequately monitored in humans. For example,dards to monitor the safety of the kidney (Serum Cre-

    N) are late and insensitive and can only be increased0% of the kidney function is lost. In the case of livernt standards (AST, ALT, Bilirubin) are not specic anddowho will recover and who will develop fulminant liverthermore, currently no accepted clinical safetymarkerse to detect andmonitor drug-induced vascular injury in

    -T Consortium (Safer and Faster Evidence-based Trans-ich is part of the Innovative Medicine Initiative (IMI),mposed of 10 pharma companies, six academic centerse, four SMEs and the European Medicine Agency, willscientic biomarker qualication strategy and apply itiomarker studies for the translation, performance test-ntual regulatory qualication of safety biomarkers fored kidney, liver and vascular injury (DIKI, DILI andDIVI).resentation, the background of this consortium, thestrategies and different steps and milestones are pre-as:

    of scientic clinical qualication processes for safetyr qualication in clinical development with healths.ization of the needs for new clinical biomarkers com-urrent standards and criteria to bemet in all three organhologies).elopment procedures: t for purpose for exploratoryltiplexed and GLP-validated for conrmatory phase.ng baseline values and their variability in healthy sub-various patient populations.and running protocols to measure the performance ofmarkers against current standards in clinical studiesital units with expected drug-induced injuries and inith relevant diseases (exploratory and conrmatory

    all three organs).

    Qualing in

    Gainstudi

    It isscienceport drand sa

    Sele

    doi:10.

    Y22Cardiatration

    CciliaBriffau

    MDS, D

    The obious bi

    Foucathetevia thewas capling.with is

    Allanimalanimalremain

    Thederivatsoftwaous timchemistropon(ASAT)A histoanimal

    Thetion ofof cardSAA, Awere tincreas

    doi:10.for Oral Presentation.

    /j.toxlet.2009.06.764

    marker evaluation following Isoprenaline adminis-he minipig

    ardy , Anne Reiniche, Olivier Boucheix, Jean-Paullne Voute

    afety Assessment, LArbresle, France

    e of the study was to investigate the pertinence of var-kers of cardiac toxicity in the minipig.tigen 10-month-old male minipigs were used. A Millaressure transducer was inserted into the left ventriclecarotid artery of each minipig. The left jugular veinrised with a polyethylene 6F catheter for blood sam-

    minipigs were maintained under general anaesthesiaane in oxygen throughout the experiment.pigs were given Isoprenaline hydrochloride. The rstived 0.5mg/kg as an intravenous bolus injection. Twoceived 6mg/kg infused intravenously over 1h. Thenimals received 0.5mg/kg by the subcutaneous route.ventricular pressure and electrocardiogram (lead IIwere continuously recorded using Notocord-hem v.3.4lood samples were taken before dosing and at vari-oints up to 150min after dosing and used for clinicaldeterminations. The parameters evaluated includedserum amyloid A (SAA), aspartate aminotransferaseine aminotransferase (ALAT) and creatine kinase (CK).ological examination of the heart was performed for all

    m levels of troponin I increased following administra-renaline and were closely correlated with the degreejury indicated in the ECG and histopathology ndings.

    and CK showed a high inter-individual variability andoorly indicative of cardiac toxicity. ASAT activity wasut this enzyme is not specic to cardiac tissue.

    /j.toxlet.2009.06.765

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