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poster BrainPlotting


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poster BrainPlotting

  1. 1. a CRO dedicated to the human brain Our core business is the study of pharmacokine5cs (PK) in the human brain at preclinical early stage. The molecules that we study can have CNS targets as well as peripheral targets. To study the brain's PK, BrainPlo[ng uses the most accurate predic5ve models and the most recent methods and tools. To generate the highest-­‐accuracy predic5ve models, BrainPlo[ng developed proprietary Purifica5on and culture of brain endothelial cells cocultured with glial cell (same sample) to maintain their BBB phenotype Permeability realised in both direc5ons (entry and exit) CLinin CLoutoutoutou Qbr Qbr Created in 2005, the « Brain and Spine Ins5tute » (ICM) is localised in Paris at the « La Pi5é Salpétriêre hospital. The bioincubator “iPEPS-­‐ICM” opened in 2012 and hosts companies involved in strong ICM partnerships, or bringing a relevant technological plaMorm to ICM. This bioincubator offers a unique environment, thanks to 500 researchers and physicians of the ICM and thanks to the Pi5e-­‐Salpetriere Hospital which is the largest hospital for the neurology in France (90,000 CNS pa5ents per year). iPEPS-­‐ICM aims at accelera5ng transla5on from ideas to products and at crea5ng a place for disrup5ve thinking. in vitro models based on primary human cells and 5ssues. PK predic5ons can be made at various stages of the molecules' development (e.g. screening, Hit-­‐to-­‐Lead, lead op5miza5on) by using a variety of methods, such as: ·∙ Evalua5on of the blood-­‐brain barrier permeability from absorp5on (blood to brain) to elimina5on (brain to blood) ·∙ Determina5on of the unbounded frac5on of the drug in the blood and in the brain ·∙ Es5ma5on of the drug concentra5on in the brain in both ECF and ICF in fresh human brain slices ·∙ Modeling the human in vivo concentra5on based on human in vitro data Determina)on of PK key parameters • CLin, CLout in humans determined with physiological in vitro models of BBB closed to in vivo situa5on à Kpu,u • Unbound frac5ons (fu) in human plasma, brain homogenate and fresh brain slices • Vu calcula5on, fu in ECF and ICF PBPK : Physiologically Based PK • Use of PK models specific to Human: Human physiological data are used in computa5onal (brain perfusion blood flow, BBB surface area, …) Brain Exposure Predic)on • Combinaison of these models & technics to predict Human brain concentra5ons • Human clinical PK informa5on from preclinical early stage Brain capillaries: 650 km lenght; 20m2 exchange area between blood and brain Blocks up to 98% of drugs Capillaries are surrounded by specific brain cells which enable the differen5a5on of endothelial cells Several transport mechanisms are described at the BBB level Crossing of a molecule results in a combina5on of all mechanisms Brain endothelial cells assume the role of BBB Brain endothelial cells Glial cells “BLOOD” “BRAIN” Isola5on of capilaries from fresh Human brains post mortem or postoperatorive Healthy and pathological 5ssues Brain extracellular space Vecf, Cecf, fu,brain ecf Brain intravascular space Viv, Civ, fu,plasma Plasma compartment Vpl, Cpl, fu,plasma Dose CLp fu,brain icf , fu,brain ecf and fu, plasma : unbound fraction into the brain intra and extracellular fluid and plasma Viv (mL/kg): physiological volume of the extravascular space Vicf and Vecf (mL/kg): physiological volume of the intra and extravascular space CL (mL/h/kg): clearances Qbr (mL/h/kg): brain perfusion blood flow Vpl (mL/kg): volume of distribution of the molecule into the plasma compartment C (ng/mL): concentration of the molecule Brain intracellular space Vicf, Cicf, fu,brain icf BBB Unbound frac5ons are determined by equilibrium dialysis in plasma, brain homogenate and brain slice which enable the dis5nc5on of ECF and ICF Cut of fresh 5ssue is performed with a vibratome (300 μM slices) Maintains structures and transport systems Claudin-­‐5 GFAP PBPK modelisa5on Contact : nicolas.perriere@brainplo[ www.brainplo[ Brain/Plasma unbound frac5on defined for your product The Blood Brain Barrier What we do and how we do it