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

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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

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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)

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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

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November 2014

Po

ten

cy

Comparison of DEI-derived dose with the DMPK predicted

dose which includes absorption and elimination

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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.

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November 2014

Further

literature

reading:

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