Macitentan – A novel sulfamide
Bosentan
Macitentan
Bolli M, et al. J Med Chem 2012; 55:7849-61.
Tissue penetration requires drugs to cross from the
bloodstream through the lipophilic cell membrane
• The ability of a drug to
cross the bilipid membrane
depends on
– Ionisation properties - drugs
cross the membrane in the
non-ionised, lipophilic form1
– Affinity for the lipid vs the
aqueous phase1
– Size of the molecule1
1. Rowland M and Tozer TN. Clinical Pharmacokinetics: Concepts and applications. Lippincott Williams & Wilkins, 1995.
Optimisation of the physicochemical properties compared
to Bosentan may favour macitentan’s penetration into
tissues: pKa
A higher pKa corresponds to greater lipophilicity and thus greater tissue targeting potential
pKa: ionisation dissociation constant
Adapted from Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.
Optimisation of the physicochemical properties
compared to Bosentan may favour macitentan’s
penetration into tissues: Log D
In vitro data
Log D (Distribution
coefficient)
Lipid:Aqueous
Macitentan
Bosentan
Ambrisentan
800:1
20:1
1:2.5
Blood
Membrane
Tissue
•
The distribution coefficient (Log D) defines the distribution of a compound
between an aqueous and a lipid phase
•
A greater affinity for the lipid phase may favour tissue penetration
•
Macitentan may have a greater affinity for the lipid phase compared with other
ERAs*
*To date, no head-to-head trials in humans have been performed.
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.
Macitentan displays sustained binding to its target
receptors
Experimental system:
Determination of changes in inhibitory potency after antagonist wash-out
(calcium flux in PASMC)
Ambrisentan
Bosentan
In vitro data
Macitentan
Kb after washout (nM)
1000
*
* * *
100
*
*
*
*
10
1
t1/2~70 sec
*
* *
t1/2~40 sec
*
*
*
*
0.1
0
20
40
60
Time after
wash-out (minutes)
*p < 0.05
*
0
t1/2~17 min
*
20
40
60
Time after
wash-out (minutes)
0
20
40
60
Time after
wash-out (minutes)
Macitentan displays a 15-fold increased receptor residence time (t1/2)
compared to ambrisentan and bosentan
Gatfield J, et al. PloS One 2012; 7(10):e47662.
In contrast to ambrisentan and bosentan, macitentan
remains potent at elevated ET-1 concentrations
Experimental system:
In vitro data
ET-1-induced signalling in human PASMCs measuring IP1
ET-1 concentration-response curves in presence of different concentrations of antagonists
Bosentan
Normalised IP1 conc. (%)
120
100
80
60
Ambrisentan
10000 nM
1000 nM
100 nM
10 nM
1 nM
0 nM
x
x
x
x
40
Macitentan
x
x
x
x
x
20
0
-11
IC50
-10
-9
-8
-7
ET-1 (log M)
-6
-5
-11
20 nM 3000 nM Inactive
Protection against
high ET-1
X
-10
-9
-8
-7
ET-1 (log M)
2 nM
-6
-5
-11
500 nM Inactive
X
-10
-9
-8
-7
ET-1 (log M)
1 nM
-6
-5
5 nM 5 nM

Gatfield J, et al. PloS One 2012; 7(10):e47662.
Chronic† macitentan administration reduced mPAP at a
dose 10-fold lower than bosentan in the MCT rat model
Animal model
+++
+++
40
* p < 0.05 vs. MCT + vehicle
*
mPAP (mmHg)
p < 0.001 vs. control
** p < 0.01 vs. MCT + vehicle
*** p < 0.001 vs. MCT + vehicle
30
***
**
***
20
***
***
***
MCT (monocrotaline)
Control
MCT + macitentan
10
MCT + bosentan
Veh 0.3
3
10
30 100 300
Dose (mg/kg/day)
†Administered
for 4 weeks
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.
Chronic† macitentan administration reduced RV
hypertrophy at a dose 10-fold lower than bosentan in
the MCT rat model
Animal model
+++
0.5
+++
p < 0.001 vs. control
* p < 0.05 vs. MCT + vehicle
** p < 0.01 vs. MCT + vehicle
*** p < 0.001 vs. MCT + vehicle
RV/LV+S
0.4
**
*
**
MCT (monocrotaline)
0.3
Control
*** ***
***
0.2
MCT + macitentan
MCT + bosentan
Veh 0.3
3
10
30 100 300
Dose (mg/kg/day)
RV: right ventricular
†Administered for 4 weeks
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.
Effect of macitentan on survival in the MCT
rat model of PAH
Animal model
100
83%
Survival (%)
80
p = 0.002
60
50%
40
Control
Monocrotaline (MCT) + vehicle
20
MCT + macitentan*
0
0
7
14
21
28
35
42
Time (days)
*macitentan was administered at 30 mg/kg/day
Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.
Raja SG. Curr Opin Investig Drugs 2010;11:1066-73.
Macitentan added to ambrisentan leads to a further
reduction in MAP
Animal model
**p < 0.05 vs. Ambrisentan then vehicle
Delta MAP (mmHg)
0
Ambrisentan
then
vehicle
Ambrisentan
then
Ambrisentan
Ambrisentan
then
Macitentan
-10
-20
-30
p = ns
-40
-50
Dahl-S rats (n = 5), telemetry equipped
Dose: 30 mg/kg (ambrisentan or macitentan) by gavage
**
Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Addition of ambrisentan to macitentan did not lead to
further reductions in MAP
Animal model
Delta MAP (mmHg)
0
Macitentan
then
vehicle
Macitentan
then
Ambrisentan
-10
-20
-30
-40
p = ns
-50
Dahl-S rats (n = 5), telemetry equipped
Dose: 30 mg/kg (ambrisentan or macitentan) by gavage
Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Macitentan added to bosentan leads to a further
reduction in MAP
Animal model
**p < 0.05 vs. Bosentan then vehicle
Delta MAP (mmHg)
0
Bosentan
then
vehicle
Bosentan
then
bosentan
Bosentan
then
macitentan
-10
-20
p = ns
-30
-40
**
-50
Dahl-Salt rat model of systemic hypertension (n = 4 to 9)
Measurements in conscious animals (telemetry)
Dose (by gavage): bosentan 100 mg/kg; macitentan 30 mg/kg
Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Addition of bosentan to macitentan did not lead to
further reductions in MAP
Animal model
Delta MAP (mmHg)
0
Macitentan
then
vehicle
Macitentan
then
bosentan
-10
-20
-30
-40
p = ns
-50
Dahl-Salt rat model of systemic hypertension (n = 4 to 9)
Measurements in conscious animals (telemetry)
Dose (by gavage): bosentan 100 mg/kg; macitentan 30 mg/kg
Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.
Pre-clinical, in vitro data and hepatic safety for
macitentan
• Inhibition of BSEP, resulting in the disruption of bile salt
homeostasis, is a key mechanism that may cause hepatic
cholestasis and liver damage1
• Macitentan and its active metabolite do not have significant
inhibitory effects on bile salt transport2,3
• In vitro studies suggest that hepatic disposition of macitentan
is mainly driven by passive diffusion rather than
OATP-mediated uptake4
1. Fattinger K, et al. Clin Pharmacol Ther 2001; 69:223-31.
2. Raja SG. Curr Opin Investig Drugs 2010; 11:1066-73.
3. Bolli M, et al. J Med Chem 2012; 55:7849-61.
4. Bruderer S, et al. AAPS 2012; 14:68-78.
Macitentan – Summary
• Macitentan is a newly developed molecule displaying:
– Optimised physicochemical properties that facilitate penetration
into the tissue
– High affinity for the ET receptors and sustained receptor binding
resulting in more effective receptor antagonism
• Pre-clinical data suggest that macitentan may have the
potential for favourable potency and efficacy
• In vitro and pre-clinical data suggests that macitentan has the
potential for favourable safety and tolerability