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[ng.com
www.brainplo[ng.com
Brain/Plasma
unbound
frac5on
defined
for
your
product
The
Blood
Brain
Barrier
What
we
do
and
how
we
do
it