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