Do we need to optimize plasma protein binding in drug discovery?

advertisement
Do We Need to Optimize Protein Binding in
Drug Discovery?
NEDMDG Summary Meeting
June 4, 2013
Xingrong Liu, Ph.D.
Genentech
Free drug interacts with drug targets: Plasma
Total IC50 = 0.3- 300x Ki
Free IC50 = 0.1-10x Ki
Liu et al., Drug Metab Dispos 37:1548–1556, 2009
100
100
80
80
SERT Occ (%)
SERT Occ (%)
Brain binding does not contribute to the
activity: free drug interacts with drug targets
60
40
20
0
-20
0.01
60
40
20
0
0.1
1
10
100
1000 10000
-20
0.01
0.1
1
10
100
1000 10000
Total Brain Concentration/KI
Unbound Brain Concentration/KI
Total IC50 = 1-1000x Ki
Free IC50 = 0.3-3x Ki
Liu et al., Drug Metab Dispos 37:1548–1556, 2009
Different effects of protein binding on in vitro
and in vivo free concentrations
In vitro
In vivo
Scenario 1
fu=0.1
fu=0.5
fu ↑
fu=0.1
fu ↑ Clin↔ fu=0.5
Cu↔
Cbound
fu=0.5
Cbound
Cbound
Cbound
Cu ↑
Cu
Cu
Scenario 2
fu ↑ Clin↓
Cu ↑
Increase of free fraction by 15X increases
IV free AUC by 3X
R2
1
1
G-378895 IV 3 mg/kg
R1
Cl
Unbound Conc. (ug/mL)
Total Conc. (ug/mL)
10
G-378242 IV 3 mg/kg
fup=0.01
0.1
R2
0.01
fup=0.15
N
G-378895 IV 3 mg/kg
G-378242 IV 3 mg/kg
0.1
0.01
0.001
R1
0.001
0.0001
0
6
12
Time (h)
18
24
0
6
12
Time (h)
• 3X increase was due to reduced clearance
18
24
Increase of free fraction by 15X increases
oral free AUC 2X
1
G-378895 PO 10 mg/kg
R2
Unbound Conc. (ug/mL)
Total Conc. (ug/mL)
10
G-378242 PO 10 mg/kg
R1
1
Cl
fup=0.01
R2
0.1
N
R1
fup=0.15
G-378242 PO 10 mg/kg
0.1
0.01
0.001
0.01
0
G-378895 PO 10 mg/kg
6
12
Time (h)
18
24
0
6
12
Time (h)
• 2X increase was due to reduced clearance
18
24
Protein binding vs. intrinsic clearance
H
N
O
O
C2H5
HN
R
O
R = -(CH2)nCH3
n = 0-8
Data form Blakey et al., J Pharmacokinet Biopharm 25:277–312, 1997
Protein binding vs. Vdss
H
N
O
 fu plasma 

Vd  Vc  Vt 
 fu tissue 
O
C2H5
HN
R
O
R = -(CH2)nCH3
n = 0-8
Data form Blakey et al., J Pharmacokinet Biopharm 25:277–312, 1997
Protein binding vs. t1/2
H
N
O
O
C2H5
HN
R
O
R = -(CH2)nCH3
n = 0-8
Data form Blakey et al., J Pharmacokinet Biopharm 25:277–312, 1997
Protein binding vs. intrinsic clearance
100000
Acids
10000
Clin (ml/min/kg)
Clin (ml/min/kg)
100000
1000
100
10
Bases
10000
1000
100
10
1
1
0.1
0.0001
0.001
0.01
0.1
0.1
0.0001
1
0.001
fu
0.1
1
fu
Neutrals
1000
10000
Clin (ml/min/kg)
Clin (ml/min/kg)
100000
0.01
1000
100
10
Zwitterions
100
10
1
0.1
0.001
0.01
0.1
fu
1
1
0.01
0.1
1
fu
Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008
Protein binding vs. Vdss
 fu plasma 

Vd  Vc  Vt 
 fu tissue 
Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008
Protein binding not associate with t1/2
Acids
10000
100
t1/2 (hr)
1000
t1/2 (hr)
Bases
1000
100
10
1
10
1
0.1
0.1
0.0001
0.001
0.01
0.1
0.01
0.0001
1
0.001
fu
1000
0.01
0.1
1
fu
Neutrals
100
Zwitterions
100
t1/2 (hr)
t1/2 (hr)
10
10
1
1
0.1
0.001
0.01
0.1
fu
1
0.1
0.01
0.1
1
fu
Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008
Brain unbound conc. is governed by the BBB and
plasma unbound conc.
Cu ,brain 
1
1
 Cu , plasma
Clefflux
PS
Clefflux: efflux transport activity at the BBB
PS: diffusion permeability at the BBB
Protein binding does not associate with
brain penetration
R2=0.077
R2=0.087
Modified from Maurer et al, Drug Metab Dispos 33: 165, 2005
Significant effects of P-gp on brain
concentration
Compound
Efflux
Compound
18
CsA
Desloratadine
14
Verapamil
8
Efflux
Digoxin
16-28
Ivermectin
14-27
Chen et al, Curr Drug Metab, 4: 272, 2003
Considerations of protein binding
in drug discovery
• No need to specifically optimize plasma binding
– Reduction of plasma protein binding alone does not increase free drug
concentration
– Reduction of clearance increases free drug concentration
– Reduction of plasma protein binding tends to associated with reduction
of clearance, as both of the parameters are governed by lipophilicity
• No need to specifically optimize brain binding
•
•
Reduction of brain tissue binding alone does not increase free brain drug
concentration
Reduction of efflux activity enhance free brain drug concentration
• Need to consider protein binding in …
– PK/PD, human PK/dose/DDI prediction, drug transporter/tissue
penetration, safety margin calculation, regulatory filing, etc.
Acknowledgements
•
Marcel Hop
•
•
Bruce Roth
Joe Lyssikatos
•
•
•
R. Scott Obach
Franco Lombardo
Nigel J. Waters
•
Dennis A. Smith
Protein binding of marketed drugs
30%
n = 267
25%
Drugs (%)
20%
15%
10%
5%
0%
<0.001
0.001-0.01 0.01-0.05
0.05-0.1
0.1-0.3
0.3-0.6
0.6-1
Unbound Fraction
n=14, fu<0.1
Data from Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th
0.0001
Modified from Maurer et al, Drug Metab Dispos 33: 165, 2005
Meprobamate
Sulpiride
Hydrocodone
Caffeine
Morphine
Metocloperamide
Methylphenidate
Lamotrigine
Buspirone
Venlafaxinec
Carisoprodol
Zolpidema
Thiopentalc
Carbamazepine
9-OH-Risperidone
Phenytoin
Risperidone
Selegiline
Diazepam
Trazodone
Propoxyphene
Citalopram
Midazolam
Hydroxyzine
Clozapine
Fluvoxamine
Cyclobenzaprine
Haloperidol
Nortriptylinea
Paroxetine
Fluoxetine
Chlorpromazine
Sertraline
Brain fu
Many successful CNS drugs show high
brain binding
1
0.1
0.01
0.001
th
io
p
ph ent
en al
yt
s u oi n
lp
ir
z o i de
lp
id
m em
or
p
tra hi n
zo e
ris do
pe ne
rid
m la m on
et
e
o c otr
lo igi
pe ne
ra
bu mid
hy s pi e
dr ron
pr o co e
op d
ox on
yp e
pa he n
ro
e
xe
s e tine
le
g
c l i li n
oz e
v e ap
nl ine
af
a
c i xin
ta
e
fl u l op
vo ram
xa
hy
m
dr
i
o x ne
no y zi
cy
ne
r
t
r
cl
ob ipty
en li n
za e
p
m fl u rine
et
h y oxe
lp ti n
he e
ni
d
h
c h al o ate
p
lo
rp eri
ro do
m
l
a
s e z ine
rtr
a
m
l
i d ine
c a azo
c a ri so lam
rb p r
a m od
az o l
ep
c a ine
et
ho ffein
su e
xi
m
di
i
az de
ep
am
AUCbrain/AUCplasma (0-5h)
240x
th
io
pe
ph nta
en l
yt
o
su in
lp
i ri
z o de
lp
id
m em
or
ph
tra i n
zo e
ris do
pe ne
rid
m la m one
et
o c otr
lo igi n
pe
ra e
bu mid
e
s
hy pir
on
dr
pr o co e
op do
ox
n
yp e
pa he n
e
ro
xe
s e tine
le
g
c l i li ne
oz
v e api
n
nl
af e
a
c i xin
ta
e
fl u l op
vo ram
xa
hy
m
i
dr
o x ne
no y zi
cy
rtr ne
cl
ob ipty
en li n
za e
pr
m fl uo ine
et
h y xet
in
lp
he e
n
ha id a
t
ch lo
p e
lo
rp erid
ro
o
l
m
az
s e ine
rtr
a
l
m
i d ine
c a azo
ri s la
m
ca
o
rb p ro
am d
az o l
ep
c a ine
ffe
di ine
az
ep
am
34x
AUCu,brain/AUCu,plasma (0-5h)
Plasma and brain binding has a significant
impact on the B/P ratio
25
20
Total Brain/Plasma Ratio
15
10
5
Acid: 0.5 (0.4-0.6)
Base: 6 ± 7 (0.1-24)
Neutral: 0.9 ± 0.7 (0.2-0.8)
0
25
20
Unbound Brain/Plasma Ratio
15
Acid: 0.2 (0.2-0.3)
Base: 1 ± 0.7 (0.1-3.4)
Neutral: 0.5 ± 0.3 (0.1-1)
10
5
0
Modified from Maurer et al, Drug Metab Dispos 33: 165, 20
Protein binding vs. clearance
Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008
Protein binding vs. free Vdss
Data form Obach et al., Drug Metab Dispos 36:1385–1405, 2008
Questions for protein binding
• PPB non-linearity – saturation of PPB as a strategy to increase
unbound concentration – is this a viable strategy?
• Covalent modifiers – does PPB even matter? Is it always total
plasma concentration?
• What about "exceptions to the rule"? - e.g. Active transport? Nonwell stirred assumption?
• Impact on Cmax and Cmin – this could be sensitive to fu – see
Derendorf paper I circulated
• Determination of unbound PK parameters (Clunbound –
Vd,ssunbound) – does this simplify or complicate things?
• Species differences?
• What should we use PPB data for in drug discovery?
Download