View
4
Download
0
Category
Preview:
Citation preview
Drug Efficiency: A New Concept to
Guide Lead Optimization Programs towards the
Selection of Better Clinical Candidates
Klara Valko et al
Analytical Chemistry, MDR
GlaxoSmithKline
United Kingdom
Efficient drugs are available at the site of action at the highest
possible free concentration with the lowest dose
Dose Solubility
Permeability
Free
Concentration
Secondary
pharmacology
Target
Silent binding sites Non-specific binding to
Proteins & phospholipids
Elimination -
Clearance
Good
absorption
Good
efficacy
Drug Efficiency Definition - Dose and Effect (PK/PD)
3
MoA
pKi
Non Specific Binding
DOSE
EFFECT
F% Abs
Vd CLb
TB PBB
Pgp Perm.
MoA pKi
BIO
PH
AS
E
AD
ME
T
iss
ue
ra
tio
DOSE
EFFECT
IN-VITRO IN-VIVO
100% xDose
ConcseFreeBiophaEfficiency
[C]
[c]
EF
FIC
IEN
CY
Comparison of potency and drug efficiency
for marketed drugs and failed candidates
-20
0
20
40
60
80
100
120
0.001 0.01 0.1 1 10 100
Fre
qu
en
cy o
f P
op
ula
tio
n
DE > 1
Marketed
Failed
0
20
40
60
80
100
120
2 4 6 8 10 12
Fre
qu
en
cy o
f P
op
ula
tio
n
pXC50 > 6
Marketed
Failed
AAPS San Diego
November 2014
Drug Efficiency Index (DEI) – a combination of efficiency and
potency
5
x100][DKd
][DTO
f ree
f ree(%)
100*Dose
BiophaseDRUGeff
Target occupancy theory
Potency DRUGeff
DEI
%TODose
1and
{
log(Dose))TO1TOlog(pKd)log(DRUG %%ef f 2
D. Montanari, E. Chiarparin,M. P. Gleeson, S. Braggio, R. Longhi, K. Valko and T. Rossi, Application of drug efficiency index in drug
discovery: a strategy towards low therapeutic dose. Expert Opinion on Drug Discovery, 6 (9) (2011) 913-920
DRUG Efficiency Index = Effective Potency
6
DEI is higher than pXC50 when the DRUGeffis >1%
Scatter Plot
DEI
3 4 5 6 7 8 9 10 11
4
5
6
7
8
9
10
11
7TM
Enzyme
Ion Channels
Nuclear
Receptors
Undefined
DRUGeff=1% pKd)log(DRUGDEI ef f
DEI
po
ten
cy
Clinical dose (mg) of marketed drugs is related to Drug
efficiency and potency (DEI)
7
100*Drug
PotencyDose
eff
K. Valko, E. Chiarparin, S.
Nunhuck, D. Montanari, In vitro
measurement of drug efficiency
index to aid lead optimization, J.
Pharm. Sci. 101(2012) 4155-4169
Drug Efficiency – Early Estimation
1. Poor bioavailability (low solubility and/or permeability, high
clearance)
2. Strong non-specific binding to proteins and phospholipids
AAPS San Diego
November 2014
8
In vivo drug distribution can be modelled by
biomimetic HPLC measurement of Human
Serum Albumin (HSA) and Immobilized
Artificial Membrane (IAM) partition
In vivo distribution of drugs
Human Clinical Volume of distribution showed good correlation to the binding difference of compounds
between phospholipids (IAM) and albumin (HSA)
Drug efficiency showed good correlation with the sum of the two types of binding (IAM + HSA) which is
the reciprocal value of the unbound volume of distribution Vdu
HSA
binding
IAM
binding
AAPS San Diego
November 2014
In vivo drug efficiency shows good
correlation with in vitro HPLC Drug eff max
Valko, K. L., Nunhuck, S. B., Hill, A.
P., Estimating unbound volume of
distribution by I n vitro HPLC-based
human serum albumin and
immobilized artificial membrane-
binding measurements. J. Pharm.
Sci., 100 (2011) 849.
Valko, K. L.,, Chiarparin, E..,
Nunhuck, S., Montanari, D., In vitro
measurements of Drug Efficiency
Index to aid lead optimization. J.
Pharm. Sci., 101 (2012) 4155. HPLC derived logVdu
AAPS San Diego
November 2014
Influence of HSA binding and IAM binding
on HPLC derived DRUGEff Max
HP
LC
DR
UG
Eff M
ax
Log k HSA
Size by: dose Colour by target class:
AAPS San Diego
November 2014
Log k IAM 7TM
Enzyme
Ion Channels
Nuclear Receptors
Undefined
Good correlation between Drug Efficiency Index (DEI)
and Ligand Lipophilicity Efficiency (LLE)
LLE =pXC50 – clogP DEI = pXC50 + log DRUGeff
Ligand Lipophilicity Efficiency (LLE)
AAPS San Diego
November 2014
Application of DEI within Lead Optimization
(green: known drugs, yellow: project compounds, red: candidates)
Red line shows when HPLC Drug eff max = 1% DEI
2 4 6 8 10 12
4
5
6
7
8
9
10
11
AAPS San Diego
November 2014
Po
ten
cy
Comparison of DEI-derived dose with the DMPK predicted
dose which includes absorption and elimination
14 AAPS San Diego
November 2014
Similar ranking of compounds were obtained for the estimated dose
McGinnity et al Curr Drug
metabolism, 2007, 8, 463.
т is the dose interval (12 h)
MEC is the minimal effective
concentration (this value can be
estimated from in vitro or in vivo data
F is bioavailability (%)
kel elimination rate (estimated from
the clearance)
Conclusions
DRUGEff summarizes the ADMET potential of a drug in a single parameter
DRUGEff Index (DEI) allows ranking compounds based on the overall balance of potency and DRUGEff
High DEI goes together in general with lower dose
High DEI can be achieved by increasing potency and/or reducing non-specific binding of compounds to proteins and lipids
Drug efficiency and DEI however, does not take into account the kinetic aspects of exposure; clearance, dosing interval, etc. We still need to optimize these parameters
This methodology allows us to introduce at the very early stages of a lead discovery and optimisation project the need for balance of the potency/availability seesaw.
15 AAPS San Diego
November 2014
Further
literature
reading:
16
Recommended