Modeling&SimulationinSystems Pharmacology...
Transcript of Modeling&SimulationinSystems Pharmacology...
Modeling&SimulationinSystems
Pharmacology
MaxvonKleist
DFGResearchCenterMATHEON
Mathematicsforkeytechnologies
April17,2014
Aboutthisseminar.
4/28
Organizationofthisseminar
⊲Goal
◮spark
interestin
SystemsPharm
acology
◮basic
concepts
◮initialexperience
5/28
Organizationofthisseminar
⊲"S
tudienleistung"
◮supervisedwork
ononestudytopic
(1-2
researcharticles+1
review)
◮asmallprogrammingtask
◮presentationofthework
(45-60min
+15min
discussion)
◮assay("schriftlicheAusarbeitung").
6/28
Organizationofthisseminar
every
thursday12:00-14:00(2x45min)
"Topicsandschedule"
date
topic
date
topic
17.04.
Overview
M.v.K.
12.06.
PD&drug-drug
interaction
M.v.K.
24.04.
Modelling
Techniques&PK
M.v.K.
19.06.
entfällt
–
08.05.
Parameter
Estimation
M.v.K.
26.06.
ODEvs.stoch.
sim
ulation
M.v.K.
15.05.
clin
.PK
&Param
est.
M.v.K.
03.07.
Drug
absorption
?
25.05.
Disease
ModellingI
M.v.K.
10.07.
PBPK
?
05.06.
Disease
ModellingII
M.v.K.
17.07.
Partition
coefficients
? 7/28
Overview.
8/28
WhatisSystemsPharm
acology?
"QuantitativeSystemsPharm
acologyisdefinedasan
approachto
translationalmedicinethatcombines
computationalandexperimentalmethodsto
elucidate,
validate
andapply
new
pharm
acologicalconcepts
tothedevelopmentanduseof[...]drugs."
Sorgeretal.QuantitativeandSystemsPharm
acologyin
thePost-genomicEra:New
Approachesto
DiscoveringDrugsand
UnderstandingTherapeuticMechanisms.NIH
WhitePaper(2011)
9/28
WhatisSystemsPharm
acology?
"QuantitativeSystemsPharm
acologyisdefinedasan
approachto
translationalmedicinethatcombines
computationalandexperimentalmethodsto
elucidate,
validate
andapply
new
pharm
acologicalconcepts
tothedevelopmentanduseof[...]drugs."
"QSPwillprovideanintegratedsystems-levelapproachto
determ
iningmechanismsofactionofnew
andexisting
drugsin
[...]patients."
Sorgeretal.QuantitativeandSystemsPharm
acologyin
thePost-genomicEra:New
Approachesto
DiscoveringDrugsand
UnderstandingTherapeuticMechanisms.NIH
WhitePaper(2011)
9/28
WhatisSystemsPharm
acology?
"QuantitativeSystemsPharm
acologyisdefinedasan
approachto
translationalmedicinethatcombines
computationalandexperimentalmethodsto
elucidate,
validate
andapply
new
pharm
acologicalconcepts
tothedevelopmentanduseof[...]drugs."
"QSPwillprovideanintegratedsystems-levelapproachto
determ
iningmechanismsofactionofnew
andexisting
drugsin
[...]patients."
"QSPwillcreate
theknowledgeneededto
change
complexcellularnetworksin
aspecifiedwaywithmonoor
combinationtherapy,[...]soasto
maxim
izetherapeutic
benefitandminim
izetoxicity[...]"
Sorgeretal.QuantitativeandSystemsPharm
acologyin
thePost-genomicEra:New
Approachesto
DiscoveringDrugsand
UnderstandingTherapeuticMechanisms.NIH
WhitePaper(2011)
9/28
ApplicationsofSystemsPharm
acology
⊲Drugdevelopment
⊲Mechanism
ofaction(throughe.g.SystemsBiology)
⊲Optimaltherapy
10/28
ApplicationsofSystemsPharm
acology
⊲Drugdevelopment
⊲Mechanism
ofaction(throughe.g.SystemsBiology)
⊲Optimaltherapy
⊲Thecomplexityoftheunderlyingprocessesandtheirdynamic
interrelationsrequiresanintegrativeapproach:
10/28
ApplicationsofSystemsPharm
acology
⊲Drugdevelopment
⊲Mechanism
ofaction(throughe.g.SystemsBiology)
⊲Optimaltherapy
⊲Thecomplexityoftheunderlyingprocessesandtheirdynamic
interrelationsrequiresanintegrativeapproach:
⇒MathematicalModelling
10/28
ApplicationsofSystemsPharm
acology
⊲Drugdevelopment
⊲Mechanism
ofaction
⊲Optimaltherapy
11/28
Drugdevelopment
cl
in
ic
al
p
ha
se
pr
e-
cl
in
ic
al
p
ha
se
targ
et
va
lid
ati
on
hit
id
en
ti-
!ca
tio
n
lea
d
ge
ne
rati
on
lea
d o
pti
-
miz
ati
on
Ph
ase
IP
ha
se I
IP
ha
se I
II
ap
pro
va
l
& m
ark
et
targ
et
dis
cov
ery
lea
d v
ali
da
-
tio
n/p
re-
clin
ica
l
test
ing
syst
em
s b
iolo
gy
che
mic
al b
iolo
gy
ne
two
rk
mo
de
llin
g
targ
et
ide
nti
!ca
tio
nsc
ree
nin
g
che
mis
try a
nim
al
stu
die
s
Ph
arm
aco
me
tric
s
tox.
PK
/PD
hu
ma
n
PK
/PD
exp
osu
re-
resp
on
se
the
rap
eu
tic
ind
ex
pa
thw
ay
& t
arg
et
sele
ctio
nco
mp
ou
nd
sele
ctio
nd
osi
ng
re
gim
en
& p
ati
en
tse
lect
ion
Op
tim
al T
he
rap
y
Me
cha
nis
m o
f A
ctio
n
12/28
Drugdevelopment
cl
in
ic
al
p
ha
se
pr
e-
cl
in
ic
al
p
ha
se
targ
et
va
lid
ati
on
hit
id
en
ti-
!ca
tio
n
lea
d
ge
ne
rati
on
lea
d o
pti
-
miz
ati
on
Ph
ase
IP
ha
se I
IP
ha
se I
II
ap
pro
va
l
& m
ark
et
targ
et
dis
cov
ery
lea
d v
ali
da
-
tio
n/p
re-
clin
ica
l
test
ing
syst
em
s b
iolo
gy
che
mic
al b
iolo
gy
ne
two
rk
mo
de
llin
g
targ
et
ide
nti
!ca
tio
nsc
ree
nin
g
che
mis
try a
nim
al
stu
die
s
Ph
arm
aco
me
tric
s
tox.
PK
/PD
hu
ma
n
PK
/PD
exp
osu
re-
resp
on
se
the
rap
eu
tic
ind
ex
pa
thw
ay
& t
arg
et
sele
ctio
nco
mp
ou
nd
sele
ctio
nd
osi
ng
re
gim
en
& p
ati
en
tse
lect
ion
Op
tim
al T
he
rap
y
Me
cha
nis
m o
f A
ctio
n
13/28
Systemspharm
.in
drugdevelopment
cl
in
ic
al
p
ha
se
pr
e-
cl
in
ic
al
p
ha
se
targ
et
va
lid
ati
on
hit
id
en
ti-
!ca
tio
n
lea
d
ge
ne
rati
on
lea
d o
pti
-
miz
ati
on
Ph
ase
IP
ha
se I
IP
ha
se I
II
ap
pro
va
l
& m
ark
et
targ
et
dis
cov
ery
lea
d v
ali
da
-
tio
n/p
re-
clin
ica
l
test
ing
syst
em
s b
iolo
gy
che
mic
al b
iolo
gy
ne
two
rk
mo
de
llin
g
targ
et
ide
nti
!ca
tio
nsc
ree
nin
g
che
mis
try a
nim
al
stu
die
s
Ph
arm
aco
me
tric
s
tox.
PK
/PD
hu
ma
n
PK
/PD
exp
osu
re-
resp
on
se
the
rap
eu
tic
ind
ex
pa
thw
ay
& t
arg
et
sele
ctio
nco
mp
ou
nd
sele
ctio
nd
osi
ng
re
gim
en
& p
ati
en
tse
lect
ion
Op
tim
al T
he
rap
y
Me
cha
nis
m o
f A
ctio
n
14/28
Contents
oftheseminar.
15/28
Contents
ofthisSeminar:I
syst
em
s b
iolo
gy
ne
two
rk
mo
de
llin
g
targ
et
ide
nti
!ca
tio
n
pa
thw
ay
& t
arg
et
sele
ctio
n
Modellingsignalling
networks
16/28
Contents
ofthisSeminar:I
syst
em
s b
iolo
gy
ne
two
rk
mo
de
llin
g
targ
et
ide
nti
!ca
tio
n
pa
thw
ay
& t
arg
et
sele
ctio
n
Modellingsignalling
networks
⊲kineticmodels
AB
C
r 1
r 3r 2
16/28
Contents
ofthisSeminar:I
syst
em
s b
iolo
gy
ne
two
rk
mo
de
llin
g
targ
et
ide
nti
!ca
tio
n
pa
thw
ay
& t
arg
et
sele
ctio
n
Modellingsignalling
networks
⊲kineticmodels
⊲ODEform
alism
⊲genericmodelling
techniques
AB
C
r 1
r 3r 2
16/28
Contents
ofthisSeminar:I
syst
em
s b
iolo
gy
ne
two
rk
mo
de
llin
g
targ
et
ide
nti
!ca
tio
n
pa
thw
ay
& t
arg
et
sele
ctio
n
Modellingsignalling
networks
⊲kineticmodels
⊲ODEform
alism
⊲genericmodelling
techniques
AB
C
r 1
r 3r 2
⊲More
onsim
ulationtechniqueson26.06
16/28
Modelin
gphilo
sophies
Mechanistic
ora
l
⊲30+parameters,14variables(1
measured)
⊲parameteridentifiability
problems
17/28
Modelin
gphilo
sophies
Mechanistic
ora
l
⊲30+parameters,14variables(1
measured)
⊲parameteridentifiability
problems
Descriptive
cen
tra
lp
eri
-
ph
era
l
Do
se Fb
io *
ka
k 12
k 21
k e
V2
V1
cen
tra
l
Do
se Fb
io *
ka
k e
V1M
od
el I
Mo
del II
Par
amete
r est
imat
ion
/m
od
el se
lecti
on
⊲4-7
parameters,1-2
variables(1
measured).
17/28
Modelin
gphilo
sophies
Mechanistic
⊲manyparameters,notsuitable
forparameterestimation
⊲basedonphysiology/elementary
processes⇒
certainty
aboutthe
modelstructure
⊲allowsinter-species/inter-patient
scaling
Descriptive
18/28
Modelin
gphilo
sophies
Mechanistic
⊲manyparameters,notsuitable
forparameterestimation
⊲basedonphysiology/elementary
processes⇒
certainty
aboutthe
modelstructure
⊲allowsinter-species/inter-patient
scaling
Descriptive
⊲usedforpredictionbefore
in
vivodata
isavailable
Question:"W
hatif?"
18/28
Modelin
gphilo
sophies
Mechanistic
⊲manyparameters,notsuitable
forparameterestimation
⊲basedonphysiology/elementary
processes⇒
certainty
aboutthe
modelstructure
⊲allowsinter-species/inter-patient
scaling
Descriptive
⊲few
parameters,suitable
for
parameterestimation
⊲uncertainty
aboutthemodel
structure
⊲usually
nottransferable
⊲usedforpredictionbefore
in
vivodata
isavailable
Question:"W
hatif?"
⊲usedforevaluationofin
vivo
data
Question:"W
hatwas?"
18/28
Contents
ofthisSeminar:II
Pharmacometrics
19/28
Contents
ofthisSeminar:II
Pharmacometrics
⊲how
often?
⊲how
much?
19/28
Contents
ofthisSeminar:II
Pharmacometrics
⊲how
often?
⊲how
much?
Pharmacokinetics(PK)
"Whatthebodydoseto
thedrug"
02
46
81
01
21
41
61
82
02
22
41
0
10
0
20
0
30
0
40
05
00
75
0
10
00
Ho
urs
aft
er
last
do
se (
in p
late
au
ph
ase
)
Plasma concentration of TFV (µ g/L)
75
mg
15
0m
g
30
0m
g
60
0m
g
19/28
Pharm
acokinetics
0
2
4
6
8
10
12
14
16
18
20
22
0
50
10
0
20
0
30
0
40
0
50
0
ho
urs
aft
er
do
se
drug concentration (µg/L)
20/28
Pharm
acokinetics
0
2
4
6
8
10
12
14
16
18
20
22
0
50
10
0
20
0
30
0
40
0
50
0
ho
urs
aft
er
do
se
drug concentration (µg/L)
Ab
sorp
tio
n
Dis
trib
uti
on
Me
tab
olis
m
Exc
reti
on
21/28
DrugAbsorption
⊲intra-venous,intra-m
uscular,sub-cutaneous
⊲GI-absorption,inhalative,transderm
al
Mechanistic
Descriptive
mo
re o
n 0
3.0
7
Rowland&Tozer.Clin
icalPharm
acokineticsandPharm
acodynamics.4th
Edition.LippincottWilliams&Wilkins(2011)
22/28
DrugDistribution
⊲instantaneousdrugdistribution
⊲bloodflow-/distribution-/transporterlim
iteddistribution
Mechanistic
PB
PK
⊲PBPK:More
on10.07
⊲Partitioncoefficients:More
on
17.07
Descriptive
cen
tra
lp
eri
-
ph
era
l
Do
se Fb
io *
ka
k 12
k 21
k e
V2
V1
cen
tra
l
Do
se Fb
io *
ka
k e
V1
1-c
mp
mo
de
l--
>in
sta
nta
ne
ou
s d
rug
d
istr
ibu
tio
n
2-c
mp
mo
de
l--
>b
loo
d !
ow
-?/d
i"u
sio
n-l
imit
ed
dru
g d
istr
ibu
tio
n
23/28
Excretion&Biotransform
ation
⊲Notafocusofthisseminar
⊲Biotransform
ation:Usually
inhepatocytes,alsoenterocytes(a
bitonthe
nextseminar)
⊲Excretion:urinary,exhalation,liver→
gallbladder→
feces,non-G
Iabsorption
Rowland&Tozer.Clin
icalPharm
acokineticsandPharm
acodynamics.4th
Edition.LippincottWilliams&Wilkins(2011)
24/28
Contents
ofthisSeminar:II
Pharmacometrics
⊲how
often?
⊲how
much?
Pharmacokinetics(PK)
"Whatthebodydoseto
thedrug"
02
46
81
01
21
41
61
82
02
22
41
0
10
0
20
0
30
0
40
05
00
75
0
10
00
Ho
urs
aft
er
last
do
se (
in p
late
au
ph
ase
)
Plasma concentration of TFV (µ g/L)
75
mg
15
0m
g
30
0m
g
60
0m
g
25/28
Contents
ofthisSeminar:II
Pharmacometrics
⊲how
often?
⊲how
much?
Pharmacokinetics(PK)
"Whatthebodydoseto
thedrug"
02
46
81
01
21
41
61
82
02
22
41
0
10
0
20
0
30
0
40
05
00
75
0
10
00
Ho
urs
aft
er
last
do
se (
in p
late
au
ph
ase
)
Plasma concentration of TFV (µ g/L)
75
mg
15
0m
g
30
0m
g
60
0m
g
Pharmadynamics(PD)
"Whatthedrugdoesto
thebody"
10
11
02
10
31
04
0
20
40
60
80
10
0
% Infection prevented
Intr
ace
ll. C
on
c T
FV
−D
P [
fmo
l/1
06 c
ell
s]
EC
50
25/28
Effectsiteconcentration
pla
sma
dru
g c
on
c.ta
rge
t ti
ssu
e
(pla
sma
)ta
rge
t
cell
Q Q
r inr ou
t
blo
od
-flo
w li
mit
ati
on
?m
em
bra
ne
lim
ita
tio
n?
no
n-l
ine
ari
ty?
r 1r 2
r 3
r -1r -2
r -3a
ctiv
ate
d
com
po
un
d
rate
-lim
ita
tio
n?
no
n-l
ine
ari
ty?
NR
TI
PI,
MI,
InI,
NN
RT
I
CC
R5
,
FI
26/28
Effectsiteconcentration
pla
sma
dru
g c
on
c.ta
rge
t ti
ssu
e
(pla
sma
)ta
rge
t
cell
Q Q
r inr ou
t
blo
od
-flo
w li
mit
ati
on
?m
em
bra
ne
lim
ita
tio
n?
no
n-l
ine
ari
ty?
r 1r 2
r 3
r -1r -2
r -3a
ctiv
ate
d
com
po
un
d
rate
-lim
ita
tio
n?
no
n-l
ine
ari
ty?
NR
TI
PI,
MI,
InI,
NN
RT
I
CC
R5
,
FI
1
plasma concentration [µM]
Ste
ad
y s
tate
ph
arm
aco
kin
eti
cs
10
−3
10
−2
10
−1
10
−8
10
−7
10
−6
10
−5
10
−4
10
−3
10
−2
10
−1
10
0
10
1
10
2
e!
ect
sit
e c
on
cen
tra
tio
n [µ
M]
01
02
03
04
05
06
07
01
0−
8
10
−7
10
−6
10
−5
10
−4
10
−3
10
−2
10
−1
10
0
10
1
concentration [µM]
tim
e [
h]
do
sin
gd
osi
ng
do
sin
g
AB
26/28
Pharm
acodynamics
Mechanistic
Re
act
ion
kin
eti
cs/
Sy
ste
ms
Bio
log
y
Dis
ea
se M
od
el
⊲More
on25.05&05.06
Descriptive
Do
se-r
esp
on
se
mo
de
ls
⊲More
on12.06
27/28
Organizationofthisseminar
every
thursday12:00-14:00(2x45min)
"Topicsandschedule"
date
topic
date
topic
17.04.
Overview
M.v.K.
12.06.
PD&drug-drug
interaction
M.v.K.
24.04.
Modelling
Techniques&PK
M.v.K.
19.06.
entfällt
–
08.05.
Parameter
Estimation
M.v.K.
26.06.
ODEvs.stoch.
sim
ulation
M.v.K.
15.05.
clin
.PK
&Param
est.
M.v.K.
03.07.
Drug
absorption
?
25.05.
Disease
ModellingI
M.v.K.
10.07.
PBPK
?
05.06.
Disease
ModellingII
M.v.K.
17.07.
Partition
coefficients
? 28/28