Drug Evaluation

Pharmacokinetic and
pharmacodynamic evaluation of
macitentan, a novel endothelin
1. Pulmonary arterial
hypertension receptor antagonist for the
2.
3.
The ET system in PAH
Macitentan
treatment of pulmonary arterial
4. Conclusion hypertension
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Queen's University on 02/03/15

5. Expert opinion
Patricia N Sidharta†, Stephan Krähenbühl & Jasper Dingemanse
†
Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland

Introduction: Pulmonary arterial hypertension (PAH) is a chronic disorder of

the pulmonary vasculature characterized by elevated mean pulmonary
arterial pressure eventually leading to right-sided heart failure and premature
death. Macitentan is an oral, once-daily, dual endothelin (ET)A and ETB
receptor antagonist with high affinity and sustained receptor binding that
was approved in the USA, Europe, Canada, and Switzerland for the treatment
of PAH.
Areas covered: This review discusses the pharmacokinetics (PK) and pharma-
For personal use only.

codynamics (PD) of macitentan and its drug interaction potential based on

preclinical and clinical data.
Expert opinion: Up to date, macitentan is the only registered treatment for
PAH that significantly reduced morbidity and mortality as a combined end-
point in a long-term event-driven study. The safety profile of macitentan is
favorable with respect to hepatic safety and edema/fluid retention and may
be better than that of other ET receptor antagonists such as bosentan and
ambrisentan. The PK profile supports a once-a-day dosing regimen. Maciten-
tan has limited interactions with other drugs. Based on these characteristics
macitentan is an important new addition to the treatment of PAH.

Keywords: endothelin receptor antagonist, macitentan pulmonary arterial hypertension,

pharmacodynamics, pharmacokinetics.

Expert Opin. Drug Metab. Toxicol. [Early Online]

1. Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a hemodynamic and pathophysiological

condition affecting the pulmonary vasculature [1-3]. It is characterized by a sustained
increase of pulmonary vascular resistance, eventually leading to right heart failure
and death, if left untreated [1,4,5]. PAH may be idiopathic, inherited, or associated
with other conditions (e.g., connective tissue disease, congenital cardiac shunts, por-
tal hypertension, HIV infection, chronic pulmonary embolism, and drugs) [1,3,6,7].
The main vascular changes in PAH are vasoconstriction, smooth-muscle cell and
endothelial-cell proliferation, and thrombosis, which are probably consequences of
pulmonary endothelial-cell dysfunction or injury [8].
Guidelines for the diagnosis and treatment of PAH have been recently reviewed
at the World Symposium on Pulmonary Hypertension [3,9-11]. Treatment of PAH
aims to improve symptoms, exercise tolerance, long-term outcomes and quality of
life, to slow disease progression, and to improve survival [3,11,12]. PAH treatments

10.1517/17425255.2015.1000859 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 1

All rights reserved: reproduction in whole or in part not permitted
 P. N. Sidharta et al.

Box 1. Drug summary.

Drug name (generic)
Phase (for indication under discussion)
Indication (specific to discussion)
Pharmacology description/mechanism
of action
Route of administration
Chemical structure
Pivotal trial(s)
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Queen's University on 02/03/15
Macitentan
Marketed
Treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease
progression
Dual endothelin receptor antagonist (ETA and ETB receptors)
Oral
Sulfamide structure:
N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-
pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide
SERAPHIN (morbidity/mortality trial)

target three main pathophysiological pathways: endothelin
(ET), intracellular nitric oxide, and prostacyclin [1,13]. Many
of the treatments for PAH are associated either with insuffi-
cient efficacy or with adverse events (AEs), in some cases lim-
iting their clinical use [12,14,15]. Oral treatment with the ET
receptor antagonists (ERAs) bosentan or ambrisentan, the
PDE-5 inhibitors tadalafil or sildenafil, and the soluble gua-
nylate cyclase stimulator riociguat is recommended as first-
line treatment in mild to moderate PAH [3].
The purpose of this review is to evaluate the published lit-
erature on the pharmacokinetics (PK) and pharmacodynamics
For personal use only.
antagonism of ETA receptors, and may be necessary to obtain
optimal efficacy and safety [27,29,32-34].
ERAs are a class of orally active agents that modulate the del-
eterious activity of ET-1 in the pulmonary vasculature [13,35-38].
Treatment with approved ERAs has been shown to confer
improvements in a number of important clinical endpoints,
including exercise capacity, modified New York Heart Associ-
ation functional class, and pulmonary hemodynamics [13,35-38].
Currently licensed ERAs can be sub-classified into dual ETA/
ETB receptor antagonists and selective ETA receptor antago-
nists [39,40]. Hepatoxicity has been associated with use of

(PDs) of the ERA macitentan (Box 1) and evaluate its drug
interaction potential.
2. The ET system in PAH
A key mediator promoting endothelial dysfunction and vascu-
lar remodeling associated with PAH is ET-1, one of a family
of closely related 21-amino-acid polypeptides. As the identifi-
cation of this potent and long-lasting vasoconstrictor in 1988,
its role in vascular pharmacology has been intensely
studied [16-18]. ET-1 elicits its effects through two receptors,
that is, ETA and ETB receptors. ETA receptors are predomi-
nantly located in vascular smooth muscle cells and cardio-
myocytes and mediate contraction, whereas ETB receptors
are mainly located in vascular endothelial cells, where they
mediate vascular dilatation through nitric oxide release and
regulate ET-1 uptake and production [19-23]. Under normal
conditions there is a balance between production and clear-
ance of ET-1 in the pulmonary vascular bed. However, in
chronic diseases such as PAH, increased circulating levels of
ET-1 have been observed [24-26]. Furthermore a correlation
between disease severity and circulating ET-1 has been
reported. It has been observed that in chronic pathological sit-
uations, ETB receptors are down-regulated on endothelial
cells and up-regulated on smooth muscle cells and fibroblasts,
suggesting that both receptors are involved in mediating det-
rimental effects [18,27-29]. Furthermore, specific blockade of
ETA receptors has been observed to activate the renin-
angiotensin system potentially resulting in edema [30,31]. It is
therefore likely that in chronic PAH dual antagonism of
both ETA and ETB receptors may be superior to selective
ERAs [41]. Bosentan, a dual ERA, which was the first oral
ERA approved for the treatment of PAH, showed a dose-
dependent increase in liver enzymes in ~ 10% of patients [42].
Whereas severe or permanent liver damage has been rarely
reported, regular monitoring of liver function tests is
required [41,43]. Following reports of fatal liver injuries sitaxen-
tan was withdrawn from the market [44-47]. Treatment with the
selective ETA receptor antagonist ambrisentan does not appear
to increase the risk of liver enzyme elevation [48,49]. However,
peripheral edema was more frequently observed with ambri-
sentan when compared to dual ERAs and therefore could
hold a risk of intervention and treatment should be discontin-
ued when considered necessary [48-50]. ET-1 has a role in vari-
ous stages of embryo development and, therefore, treatment
with ERAs has been observed to cause fetal harm [51,52]. Conse-
quently, all approved ERAs hold a black-box warning for
embryo-fetal toxicity and must not be administered to preg-
nant females [50,53]. Furthermore, ERAs have been associated
with decreases in hemoglobin and sperm count [50,53].
3. Macitentan
Macitentan is an oral, once-daily, potent dual ETA/ETB recep-
tor antagonist that was granted approval for the treatment of
PAH patients by the US FDA, the European Medicines
Agency (EMA), Health Canada, and Switzerland in October,
November, and December 2013, and February 2014,
respectively [54-56]. The approval was largely based on the data
from the landmark Phase III Study with an ERA in PAH to
Improve Clinical Outcome (SERAPHIN) study. SERAPHIN
was a long-term, randomized, placebo-controlled study in

2 Expert Opin. Drug Metab. Toxicol. (2014) 11(3)


PAH patients with a clearly defined morbidity/mortality pri-
mary endpoint designed to evaluate the efficacy and safety of
macitentan [57,58]. Two dose levels were studied in SERA-
PHIN. Macitentan reduced the risk of a morbidity/mortality
event versus placebo (10 mg dose, risk reduction 45%,
p < 0.001; 3 mg dose, risk reduction 30%, p = 0.01) [57]. Maci-
tentan appeared to be well tolerated at both dose levels; the
number of AEs reported and of patients discontinuing treat-
ment due to AEs was similar across all treatment groups and
the frequency of liver enzyme elevations was comparable
between the macitentan and placebo groups [57].
Current guidelines for clinical research on PAH support
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Queen's University on 02/03/15
the use of these long-term outcome studies and SERAPHIN
showed that conducting large-scale, powered, clinical studies
using morbidity/mortality endpoints is feasible. A thorough
discussion of the study and its limitations is provided by
Pulido et al. as well as by Dingemanse et al. [57,58].
As discussed previously, ERAs may cause fetal harm and,
therefore, macitentan must not be administered to pregnant
females and appropriate methods of contraception should be
applied [59]. Similar to other ERAs a decrease in hemoglobin
was observed in patients treated with macitentan [57,58]. Maci-
tentan did not affect fertility in vitro [59]. However, as other
ERAs caused an effect on spermatogenesis an adverse effect
For personal use only.
with treatment of macitentan cannot be excluded [59].
A comprehensive evaluation of the safety profile of maciten-
tan has been provided by Dingemanse et al. [58].
3.1 Chemistry and preclinical development
Macitentan ({N-[5-(4-bromo-phenyl)-6-[2-(5-bromo-pyri-
midin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-N’-propylamino-sul-
famide) (Figure 1) resulted from an extensive and targeted
discovery program with the objective to develop an ERA
with high oral efficacy while reducing the safety risks found
O O
S
NH
Br
N
H olite ACT-132577 have been extensively studied in several
N
O N
N O
N In healthy male subjects, after single-dose administration of
Br
O 0.2 -- 600 mg, macitentan was slowly absorbed with a median
O
S Br
NH
H2 N
N (Table 1) [65]. Plasma concentration versus time profiles after
O N
N O
N between ~ 40 and 66 h (Table 1). After multiple-dose adminis-
Br
Figure 1. Chemical structures of macitentan (upper) and ACT
-132577 (lower).
Expert Opin. Drug Metab. Toxicol. (2014) 11(3)
Macitentan
with other ERAs [60]. Unlike other ERAs such as bosentan
and sitaxentan, it does not have a sulfonamide structure and
belongs to the class of sulfamides. Macitentan is highly potent
on the ETA receptor with a significant affinity to the ETB
receptor as demonstrated in preclinical studies [60,61].
Although in vitro data on ETA versus ETB potency suggest a
higher affinity of macitentan for ETA, these tests were per-
formed in the presence of plasma proteins [61]. When consid-
ering the free inhibitory concentrations (IC50) for ETA and
ETB, observed values were within the range of free concentra-
tions observed in humans treated with macitentan at the ther-
apeutic dose of 10 mg suggesting that ETB blockade is
achieved [61,62]. This has been further confirmed in vivo by
an observed increase in ET-1 plasma concentrations typical
of treatment with a dual ERA and not a selective ERA [61].
In preclinical models of hypertension and PAH, macitentan
showed a dose-dependent decrease in mean arterial blood
pressure, without affecting heart rate [60,61]. The physicochem-
ical properties of macitentan were optimized to facilitate pen-
etration into the tissue, which contributes to superior in vivo
pharmacological efficacy compared with other ERAs. Indeed,
Iglarz et al. showed that in preclinical models of systemic
hypertension and pulmonary hypertension, macitentan on
top of the ERA bosentan further reduced blood pressure,
whereas this was not the case when bosentan was given on
top of macitentan [63]. Tissue targeting was achieved through
an increase in pKa and log D values resulting in a higher affin-
ity of macitentan for lipophilic structures [61]. In addition,
macitentan has sustained receptor binding resulting in opti-
mized ET receptor antagonism [64]. In vitro, compared to
other ERAs such as bosentan and ambrisentan, macitentan
had a slow apparent receptor association rate and a 15-fold
extended receptor occupancy half-life. Only macitentan dis-
played insurmountable antagonism, which could lead to a
more effective blockade of ET-1 compared to other ERAs [64].
3.2 PKs in healthy subjects
The PKs and metabolism of macitentan and its active metab-
Phase I studies in healthy subjects. In addition, the PKs
were assessed also in special populations such as patients
with renal or hepatic impairment, as well as in a sub-
population of the Phase III SERAPHIN study.
tmax varying from 8 to 30 h (Table 1). Thereafter, concentra-
tions decreased slowly with an approximate half-life of 16 h
single-dose administration are shown in Figure 2. The active
metabolite ACT-132577 was slowly formed with a half-life
tration of macitentan at doses ranging from 1 to 30 mg, the PKs
of both macitentan and ACT-132577 were consistent with
those observed in the single-ascending dose study (Figure 3),
with half-lives of ~ 16 and 48 h, respectively (Table 2).
3
 P. N. Sidharta et al.

Table 1. Single-dose pharmacokinetics of macitentan and its active metabolite ACT-132577 in healthy subjects
following oral administration.

Dose (mg) N Macitentan

Cmax tmax AUC0 -- 48 AUC0 -- ` t1/2

(ng/ml) (h) (ng.h/ml) (ng.h/ml) (h)

0.2 6 4.0 8 85.9 ND ND

(2.6, 6.2) (8 -- 12) (52.4, 141)
1 6 17.9 8 439 ND ND
(12.4, 25.9) (4 -- 10) (271, 711)
5 6 93.4 8 2056 ND ND
(79.1, 110) (4 -- 8) (1855, 2278)
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25 6 335 8 8810 ND ND
(264, 425) (4 -- 30) (7412, 10472)
100 6 999 8 25281 ND ND
(643, 1552) (4 -- 12) (18775, 34040)
300 6 1847 30 67109 103007 17.5
(1409, 2422) (10 -- 48) (48751, 92380) (76650, 138428) (14.1, 21.8)
600 5 2967 12 96530 127104 13.4
(2233, 3943) (8 -- 30) (70006, 133102) (82657, 195450) (11.3, 15.9)

ACT-132577

Cmax tmax AUC0 -- 48 AUC0 -- ` t1/2

(ng/ml) (h) (ng.h/ml) (ng.h/ml) (h)

0.2 6 3.7 36 114 ND ND

For personal use only.

(2.6, 5.2) (30 -- 48) (77.8, 168)

1 6 16.3 48 527 ND ND
(12.6, 21.2) (30 -- 48) (415, 670)
5 6 84.1 33 2540 ND ND
(74.2, 95.4) (30 -- 48) (2117, 3048)
25 6 304 42 9146 ND ND
(271, 342) (30 -- 48) (7297, 11463)
100 6 931 42 32068 ND ND
(674, 1287) (30 -- 48) (22727, 45249)
300 6 2585 48 67174 330549 65.6
(1759, 3798) (48 -- 72) (45343, 99515) (257489, 424340) (53.1, 80.9)
600 5 3688 48 104968 342084 40.2
(2591, 5249) (36 -- 48) (73339, 150238) (213414, 548331) (34.6, 46.7)
Data are expressed as geometric means (and 95% CI) or for tmax the median (and range). ND because t1/2 could not be reliably assessed.
AUC: Area under the plasma concentration versus time curve; ND: Not determined; t1/2; Apparent terminal elimination half-life.

The observed long half-lives of macitentan and ACT-132577
could be a reflection of slow receptor dissociation kinetics and
tissue targeting properties of macitentan as described by
Gatfield et al. and Iglarz et al. [61,64] Steady-state conditions
were reached on Day 3 for macitentan and Day 7 for
ACT-132577. Accumulation of macitentan after multiple-
dosing was limited with an accumulation factor of 1.5, whereas
ACT-132577 accumulated substantially leading to an increase
in its exposure between Day 1 and steady-state of 8.5-fold
on average (Table 2) [62]. The PKs of macitentan and
ACT-132577 were dose-proportional over the range
1 -- 30 mg and supported once-daily dosing [62]. The PKs of
macitentan and ACT-132577 were not influenced by
food [59]. No formal study was performed to investigate the
oral bioavailability of macitentan, but data from physiologically
based PK modeling indicated a high oral bioavailability of
macitentan, also observed in animals (Actelion Pharmaceuticals
Ltd, data on file). Macitentan can be regarded as a low extrac-
tion drug. After administration of 10 mg macitentan to Japa-
nese female and male healthy subjects, for both macitentan
and the metabolite ACT-132577 a similar maximum plasma
concentration with a slighty shorter-half life was observed com-
pared to Caucasian subjects [66]. This resulted in a decrease in
exposure of ~ 15% in Japanese subjects. When comparing the
PKs in males and females, the exposure to macitentan was sim-
ilar in Japanese males and females, whereas exposure to maci-
tentan was slightly higher in Caucasian women when
compared to Caucasian men. The exposure to ACT-132577
was ~ 15% higher in all women, independent of race, when
compared to men [66]. Similar PK properties were observed in
Korean subjects in a multiple dosing regimen with
macitentan [67].

4 Expert Opin. Drug Metab. Toxicol. (2014) 11(3)

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For personal use only.

10000 10000
3000 6000 600 mg
1000 300 mg 1000
100 mg
2500 100 25 mg 100
5 mg

(ng/ml)

(ng/ml)
10 10
1 mg
2000 1
4000 0.2 mg 1

Macitentan concentration
ACT-132577 concentration
0.1 0.1
1500 0 24 48 72 96 120 144 0 24 48 72 96 120 144
Time after administration (h) Time after administration (h)

1000 600 mg
300 mg 2000
100 mg
25 mg
500 5 mg
1 mg

Macitentan concentration (ng/ml)

ACT-132577 concentration (ng/ml)
0.2 mg

0 0
0 24 48 72 96 120 144 0 24 48 72 96 120 144
Time after administration (h) Time after administration (h)

Figure 2. Arithmetic mean plasma concentration--time profiles of macitentan (left) and its metabolite, ACT-132577 (right) in healthy subjects (n = 6 per group except for 600 mg
dose where n = 5) after administration of a single dose of 0.2, 1, 5, 25, 100, 300 or 600 mg of macitentan. The semilogarithmic scale is shown as an insert within each panel.

1000 10000
1000 3000
100 1000

800 10 100

(ng/ml)
(ng/ml)

Expert Opin. Drug Metab. Toxicol. (2014) 11(3)

1 2000 10
600
0.1

Macitentan concentration
1
ACT-132577 concentration

0 48 96 144 0 48 96 144 192 240

Time after administration on Time after administration on
400 day 10 (h) day 10 (h)
1000 30 mg
30 mg 10 mg
200 10 mg 3 mg
1 mg
3 mg

Macitentan concentration (ng/ml)

ACT-132577 concentration (ng/ml)

1 mg
0
0 48 96 144 192 240 0
0 48 96 144 192 240
Time after administration on day 10 (h)
Time after administration on day 10 (h)

Figure 3. Arithmetic mean (±SD) plasma concentration--time profiles of macitentan (left) and its metabolite, ACT-132577 (right) in healthy subjects (n = 6 per dose
group) after once-daily administration of 1, 3, 10, and 30 mg of macitentan for 10 days. The semilogarithmic scale is shown as an insert within each panel.
Macitentan

5
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For personal use only.

6
P. N. Sidharta et al.

Table 2. Multiple-dose pharmacokinetics of macitentan and its active metabolite ACT-132577 in healthy subjects following oral administration for 10 days.

Dose Day MACITENTAN ACT-132577

(mg)
Cmax tmax AUCt t1/2 Accumulation Cmax tmax AUCt t1/2 Accumulation
(ng/ml) (h) (ng.h/ml) (h) index (ng/ml) (h) (ng.h/ml) (h) index

1 mg 1 22.7 8.0 329 14.4 24.0 209

(19.0, 27.0) (6.0 -- 12.0) (275, 393) (12.0, 17.2) (24.0 -- 24.0) (162, 269)
10 30.2 8.5 471 15.2 1.4 73.0 10.0 1483 46.6 7.1
(23.2, 39.3) (6.0 -- 10.0) (352, 631) (11.5, 20.1) (1.3, 1.6) (63.7, 83.7) (8.0 -- 12.0) (1306, 1684) (43.1, 50.4) (5.9, 8.6)
3 mg 1 67.2 7.5 1004 36.5 24.0 511
(57.5, 78.5) (7.0 -- 8.0) (864, 1165) (28.6, 46.6) (24.0 -- 24.0) (389, 672)
10 106 8.0 1722 18.5 1.7 247 8.0 5048 55.8 9.9
(80.3, 141) (7.0 -- 9.0) (1201, 2469) (13.8, 24.9) (1.4, 2.2) (178, 343) (1.0 -- 12.0) (3602, 7074) (43.7, 71.3) (7.5, 13.0)
10 mg 1 261 8.0 3571 143 24.0 2206
(200, 341) (6.0 -- 12.0) (2649, 4813) (113, 181) (12.0 -- 24.0) (1733, 2807)
10 371 6.0 5400 13.7 1.5 802 9.0 15541 43.0 7.1
(290, 475) (5.0 -- 12.0) (4107, 7099) (11.4, 16.5) (1.4, 1.7) (585, 1100) (8.0 -- 12.0) (11931, 20244) (40.4, 45.9) (6.4, 7.8)

Expert Opin. Drug Metab. Toxicol. (2014) 11(3)

30 mg 1 465 10.0 7449 296 24.0 4152
(369, 587) (7.0 -- 16.0) (6090, 9112) (190, 461) (24.0 -- 24.0) (2499, 6901)
10 790 8.0 13000 14.3 1.7 1927 8.5 40181 47.0 9.7
(662, 943) (5.0 -- 9.0) (10665,15845) (12.8, 16.1) (1.4, 2.2) (1361,2730) (8.0 - 10.0) (28302, 57047) (42.1, 52.5) (6.3, 15.0)

Data are geometric means (95% CI) or median (range) for tmax. n = 6 per dose group.
AUC: Area under the plasma concentration versus time curve; Cmax: Maximum plasma concentration; tmax: Time to reach maximum plasma concentration; t1/2: Apparent terminal elimination half-life.

Macitentan and its metabolite are highly bound (> 99%) to
plasma proteins; mainly albumin and the same observations
were made in subjects with renal or hepatic impairment [68,69].
In human plasma, two circulating metabolites have been identi-
fied [68]. The active metabolite ACT-132577 is formed by oxida-
tive depropylation catalyzed mainly by CYP 3A4 with minor
contribution of CYP2C19. The pharmacologically inactive
metabolite ACT-373898 is formed by oxidative cleavage. After
single-dose administration in healthy subjects used as a control
group for comparison with subjects with renal or hepatic
impairment, total plasma exposure to macitentan,
ACT-132577, and ACT-373898 was, on average, ~ 24, 74,
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Queen's University on 02/03/15
and 2%, respectively [69]. Besides CYP3A4, minor contributors
to macitentan clearance are CYP2C8, CYP2C9, and
CYP2C19. Metabolites subsequently undergo further reactions
to form additional metabolites that are excreted in urine and
feces. Neither macitentan nor ACT-132577 was detected in
urine. Major entities in urine were ACT-373898, the hydrolysis
product of ACT-373898, and a conjugation product of
ACT-132577 with glucose [68]. In feces, five entities were
detected: macitentan, ACT-132577, ACT-373898, and the
hydrolysis products of ACT-373898 and ACT-132577 [68].
Based on the observed slow absorption, indicating low solubility
of macitentan and high permeability observed in the absorption,
For personal use only.
metabolism, distribution, and elimination study, macitentan
belongs to class II using the biopharmaceutical classification
system [70].
3.3 PKs in patients
PK studies performed in renally or hepatically impaired patients
revealed no clinically relevant differences in macitentan or
ACT-132577 PKs [69]. After single-dose administration of
10 mg macitentan, exposure to macitentan and
ACT-132577 was generally lower with decreases of up to 34%
in subjects with hepatic impairment when compared to healthy
subjects, although no correlation with the degree of hepatic
impairment was observed. Exposure to ACT-373898 was only
lower (geometric mean ratio and 90% confidence interval of
0.65 [0.47 -- 0.90]) in subjects with mild hepatic impairment [69].
The findings of this study indicate that, based on PK observa-
tions, no dose adjustments would be needed in patients with
hepatic impairment. Due to the lack of clinical experience with
the use of macitentan in PAH patients with moderate or severe
hepatic impairment, the use of macitentan in patients with
severe hepatic impairment is contraindicated and patients with
an increase in hepatic aminotransferases more than three times
the upper limit of normal at baseline [71]. Exposure to maciten-
tan and ACT-132577 in subjects with severe renal impairment
only marginally differed from that observed in healthy subjects.
However, exposure to the inactive metabolite ACT-373898 was
approximately seven fold of that observed in healthy subjects,
suggesting that this metabolite is predominantly cleared by the
kidney. ACT-373898 is pharmacologically inactive and suffi-
cient safety margins were established in the toxicology program,
and no safety concerns were raised in the study. Therefore, based
Expert Opin. Drug Metab. Toxicol. (2014) 11(3)
Macitentan
on PKs, no dose adjustment is indicated [69]. Patients on dialysis
have not been included in clinical studies, and, therefore, maci-
tentan is not recommended in such patients [71].
In the SERAPHIN study, in a sub-population, PK samples
were collected at trough. In addition, a PK profile over 24 h at
steady state was obtained from 20 patients treated with 10 mg
macitentan in the open-label extension study of SERAPHIN
(Actelion Pharmaceuticals Ltd, data on file). Data indicated
that the exposures to macitentan and its active metabolite in
PAH patients were similar to those observed in healthy
subjects [59].
3.4 Drug interaction potential
A recent publication by Weiss et al. suggested that in vitro
macitentan was an inducer of CYP3A4 as well as an inducer
and inhibitor of several transporters such as P-glycoprotein
(P-gp) [72]. However, further in vitro and in vivo studies, per-
formed at clinically relevant concentrations, showed that
macitentan is not a substrate of P-gp [59]. Hepatic uptake is
mostly driven by passive diffusion and is not dependent on
organic anion-transporting polypeptide (OATP) transport
unlike other ERAs such as bosentan [73-75]. The limited drug
interaction potential of macitentan was demonstrated in a
number of drug--drug interaction studies and is summarized
in Table 3.
In a drug--drug interaction study with warfarin, an antico-
agulant that is frequently used in the treatment of PAH, maci-
tentan did not affect the PK of both R- and S-warfarin
resulting in geometric mean ratios close to 1 [76]. Likewise,
the PD parameters international normalized ratio (INR) and
factor VII activity (a vitamin K-dependent coagulation factor)
were not affected by macitentan in this study [76]. These data,
therefore, indicate that at clinically relevant concentrations
macitentan does not inhibit or induce CYP1A2 or CYP2C9,
the enzymes that are relevant in the metabolism of warfarin.
In the presence of ketoconazole exposure to single-dose
macitentan increased approximately two fold, with a decrease
in exposure to ACT-132577 by 26% [77]. The limited impact
of a strong CYP3A4 inhibitor on the PKs of macitentan sup-
ports the finding that metabolism of macitentan is not solely
dependent on CYP3A4. Whereas effects on macitentan of
other strong CYP3A4 inhibitors such as ritonavir were not
studied clinically, it is likely that a similar increase in maciten-
tan exposure would occur as seen with ketoconazole. In the
presence of ketoconazole the observed exposure to macitentan
after single-dose administration and the simulated exposure to
macitentan after multiple-dose administration were in the
range of exposures observed in the single- and multiple-dose
studies at higher doses of macitentan. As long-term safety
data during use of such a combination are currently lacking,
the clinical relevance of these observations is not completely
clear and concomitant treatment with strong inhibitors of
CYP3A4 should be used with caution [59,71].
When administered with the moderate CYP3A4 inhibitor
cyclosporine, exposure to macitentan and its metabolites
7
 P. N. Sidharta et al.

Table 3. Geometric mean ratios and 90% confidence intervals of Cmax, Ctrough, AUC0 -- `, or AUCt values in the
presence and absence of interacting drugs.

Substrate Interacting drug Ratio of geometric means (90% CI)*

Cmax Ctrough AUC0 -- ` AUCt

Macitentan Sildenafil 0.99 (0.92, 1.06) -- -- 1.06 (1.01, 1.12)

ACT-132577 0.82 (0.76, 0.89) -- -- 0.85 (0.80, 0.91)
Macitentan Cyclosporine-A -- 1.38 (1.06, 1.81) -- 1.10 (0.91, 1.33)
ACT-132577 -- 1.02 (0.87, 1.19) -- 0.97 (0.85, 1.11)
Macitentan Ketoconazole 1.30 (1.20, 1.40) -- 2.30 (2.10, 2.50) --
ACT-132577 0.49 (0.43, 0.56) -- 0.74 (0.66. 0.84) --
Macitentan Rifampin -- 0.07 (0.05, 0.10) -- 0.21 (0.17. 0.26)
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Queen's University on 02/03/15

ACT-132577 -- 0.83 (0.73, 0.94) -- 1.00 (0.89, 1.12)

R-warfarin Macitentan 0.97 (0.92, 1.03) -- 1.00 (0.94, 1.05) --
S-warfarin 0.94 (0.85, 1.04) -- 1.01 (0.96, 1.05) --
Sildenafil Macitentan 1.26 (1.07, 1.48) -- -- 1.15 (0.94, 1.41)
N-desmethyl sildenafil 1.10 (0.99, 1.22) -- -- 1.08 (0.96, 1.22)

*Ratio relative to treatment with substrate only.

only changed marginally with geometric mean ratios close to
1 [75]. The data of this study concur with the preclinical data
that macitentan is not dependent on OATP transport.
Induction of CYP3A4 with the strong inducer rifampin
resulted in a decrease in exposure to macitentan of ~ 80%.
For personal use only.
marketed drugs [81] and the concomitant use of medications
metabolized by CYP3A4 such as calcium antagonists, new
oral anticoagulants, and hormonal contraceptives in the treat-
ment of PAH [13,82].
Overall, the data of the clinical studies suggest that maci-

Exposure to the active metabolite ACT-132577 was not
affected by rifampin [75]. Macitentan and its metabolite
ACT-132577 are both potent dual ERAs, and both contrib-
ute to the overall pharmacological effect of macitentan
in vivo. ACT-132577 is approximately five fold less potent
than macitentan in vitro but has a higher systemic exposure
in humans [61,78]. As the decrease in exposure to macitentan
in the presence of rifampin may affect the overall pharmaco-
logical effect of the drug, reduced efficacy is probable and
should be taken into account. Therefore, the concomitant
use of macitentan with strong CYP3A4 inducers should be
avoided [59,71].
Investigation of the mutual PK interaction between maci-
tentan and sildenafil indicated no clinically relevant impact
on either drug [79]. Maximum plasma concentrations of and
exposure to macitentan during a dosing interval were not
affected by sildenafil with geometric mean ratios and 90%
CI close to 1. Exposure to the active metabolite
ACT-132577 decreased by ~ 15% in the presence of sildena-
fil, which, considering the difference in potency to macitentan
and the inter-individual variability, is not clinically relevant.
In the presence of macitentan, plasma concentrations of sil-
denafil were higher than during treatment with sildenafil
alone, resulting in an increase in exposure by ~ 15%. The
PKs of N-desmethylsildenafil were not affected by maciten-
tan. As sildenafil is listed as a sensitive model substrate to
study CYP3A4-mediated drug--drug interactions [80], these
results indicate that macitentan is unlikely to affect the PKs
of other substrates of CYP3A4 to a clinically relevant extent.
This is an important finding in view of the fact that
CYP3A4 is involved in the metabolism of about 50% of
tentan has a favorable drug--drug interaction profile [73,83-90].
3.5 Pharmacodynamics
In the phase I program, ET-1 and bile salt concentrations
were investigated. Plasma ET-1 concentrations increased in
a dose-dependent manner up to the highest single dose of
600 mg macitentan [65]. At the highest dose in the single-
ascending dose study, an increase in ET-1 levels of 2.2-fold
(95% CI: 1.4 -- 3.4) was observed compared to placebo.
This increase was similar to that observed with bosentan,
with macitentan having a greater potency [65,91]. The dose-
dependent increase in ET-1 was also observed under steady-
state conditions in the multiple-ascending dose study [62].
The maximum effect, which was approximately an increase
of two fold, was observed with a dose of 10 mg macitentan
once daily. ET-1 levels did not further increase at a dose level
of 30 mg macitentan, which supported the choice of 10 mg
macitentan in further clinical studies [62]. In a study in healthy
Korean subjects ET-1 plasma concentrations increased to a
similar extent as in Caucasians, following multiple-dose
administration of macitentan [67]. This indicates that ethnic
differences probably do not impact the efficacy of macitentan.
Macitentan did not affect systemic blood pressure in
healthy subjects, although the duration of treatment was likely
too short to observe any effect [65,69]. No data on the effects of
macitentan on systemic blood pressure in PAH patients
are described.
ERAs have thus far only been approved for the treatment of
PAH and digital ulcers associated with systemic sclero-
sis [35,92,93]. This is also due to the fact that they are associated
with liver injury, necessitating close monitoring of liver

8 Expert Opin. Drug Metab. Toxicol. (2014) 11(3)


function [39]. In fact, sitaxentan, a selective ETA receptor
antagonist, was withdrawn from the market due to occurrence
of severe idiosyncratic liver injury [45-47,94].
Inhibition of the bile salt export pump, an ABC transporter
protein mediating secretion of bile salts across the canalicular
plasma membrane of hepatocytes, thus resulting in intracellu-
lar accumulation of bile salts and subsequent liver injury, has
been proposed as a possible mechanism for hepatic adverse
reactions with bosentan [95-97]. In preclinical models the
ERAs sitaxentan and bosentan were substrates of human
hepatic transporters and inhibited these transporters [98]. In
the same models, at clinically relevant concentrations, maci-
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Queen's University on 02/03/15
tentan did not show such inhibition, suggesting that maciten-
tan may not induce bile salt retention and hepatocellular liver
injury [74]. Indeed, macitentan did not affect serum bile salt
concentrations of animals at very high dose levels and no rel-
evant increases in serum bile salts occurred in humans at sin-
gle and multiple doses of up to 600 and 30 mg once daily,
respectively [62,65,74].
PK/PD modeling was performed on data obtained from
the SERAPHIN study, which have currently been published
in abstract form. At month 6, in a subgroup of the study pop-
ulation, PK samples were taken at trough [99] and correlated
with other collected data such as hemodynamics, AEs, and
For personal use only.
liver enzyme activity. The PK/PD analysis suggested that
higher macitentan concentrations were associated with a
reduction in pulmonary vascular resistance, mean pulmonary
artery pressure, and total pulmonary resistance as well as an
increase in the cardiac index and 6-min walking distance [99].
No relationship could be established between macitentan con-
centrations and mean right atrial pressure, mixed venous oxy-
gen saturation, hematocrit, hemoglobin, or alanine/aspartate
aminotransferase levels. Macitentan concentrations were also
not associated with the probability of the occurrence of an
AE leading to study drug discontinuation.
In conclusion, no clear PK/PD relationship could be deter-
mined between macitentan trough concentration and safety
parameters. For efficacy parameters, however, modeling
showed that macitentan improved hemodynamic parameters
and exercise capacity in a concentration-dependent manner
in patients with PAH [99].
The effect of macitentan on the QT/QTc interval was eval-
uated in a thorough QT study [100]. The study was performed
as a double-blind, randomized, placebo- and positive-con-
trolled, crossover study in 64 healthy male and female sub-
jects. Each subject received treatments that consisted of:
i) placebo; ii) 400 mg moxifloxacin (positive control);
iii) macitentan 10 mg (therapeutic dose; and iv) macitentan
30 mg (supra-therapeutic dose). The QT correction using
the Fridericia method (QTcF) was identified as the most
appropriate heart rate correction. The upper bound of the
two-sided 90% CI of the least square mean (LSM) for
DDQTcF (equivalent to the one-sided 95% CI) was < 10 ms
at each timepoint of assessment for each macitentan dose
measured over a 24 h period under steady-state conditions
Expert Opin. Drug Metab. Toxicol. (2014) 11(3)
Macitentan
(maximum of 7.6 and 7.3 ms with macitentan 10 and
30 mg, respectively). Assay sensitivity was demonstrated by a
clear QT prolongation effect following administration of
400 mg moxifloxacin (positive control). The LSM estimates
of DDQTcF were between 11.9 and 12.6 ms and the lower
bound of the two-sided 90% CI of the LSM for DDQTcF
ranged between 9.5 and 10.2 ms [100]. The categorical analysis
of QT intervals did not show any prolongation to > 500 ms or
changes from baseline of > 60 ms in the cardiodynamic assess-
ments. Single occurrences of QT prolongation to > 450 ms
and changes from baseline of > 30 ms were randomly distrib-
uted across all treatments including placebo [100].
4. Conclusion
Macitentan is a dual ETA/ETB receptor antagonist and repre-
sents a new category of ERAs due to its optimized physico-
chemical properties resulting in enhanced tissue penetration
and sustained receptor occupancy compared to currently mar-
keted ERAs such as ambrisentan and bosentan. Both maciten-
tan and its pharmacologically active metabolite
ACT-132577 have a long half-life, which supports a once-
daily dosing regimen. The PKs of macitentan do not substan-
tially differ in patients with PAH or subjects with renal or
hepatic impairment. Also, in comparison to other ERAs it
has a low potential for clinically important drug--drug interac-
tions. Macitentan is not a substrate of liver drug transporters,
and no elevations in bile salts were observed in animals and
humans after macitentan administration. Recently, maciten-
tan has been approved by US FDA, EMA, Switzerland, and
Health Canada after completion of the first large-scale mor-
bidity/mortality study with a long-term outcome. In this
study it was shown that the risk of morbidity and mortality
in PAH was significantly reduced in both treatment-naive
patients as well as in those on background PAH therapy.
5. Expert opinion
Macitentan is a recently approved dual ERA for the treatment
of PAH. Its dual receptor antagonism is shared with bosentan,
whereas ambrisentan is an ETA-selective receptor antagonist.
ERAs have acquired an established place in the pharmacolog-
ical treatment of PAH since their introduction at the begin-
ning of the century. Macitentan has undergone one of the
largest Phase III studies conducted in this field and used a
composite morbidity/mortality primary endpoint, consisting
of clinically highly relevant components. With respect to
drug concentrations and PD properties, macitentan showed
in both healthy subjects as well as hypertensive and PAH
patients that a low dose of 10 mg is effective.
With respect to its PK properties, macitentan has shown
low variability, commonly seen for compounds being metab-
olized to an active moiety with a relatively long elimination
half-life. This latter metabolite, ACT-132577, is the only
metabolite with pharmacological activity at the ET receptors
9
 P. N. Sidharta et al.

and is anticipated to contribute ~ 50% to the overall activity
following administration of macitentan. The elimination
half-life of macitentan and ACT-132577 is ~ 16 h and
48 h, respectively. Besides a clear once-a-day profile, this ren-
ders macitentan the characteristics of a ‘forgiving’ drug, that
is, the drug’s efficacy is not expected to be affected when a
patient forgets to take a dose of macitentan.
Further important features are that the PKs of macitentan
are dose-proportional and appear not to be significantly influ-
enced by food, sex, ethnic origin, age, stage of PAH disease
(functional class) or presence of hepatic or renal disease. Maci-
tentan is a low clearance drug, which means it is less sensitive
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Queen's University on 02/03/15
the absence of inducing or inhibiting CYP3A4 proves further
advantages of macitentan. Macitentan has, generally, been
well tolerated. AEs were usually mild and mostly not dose-
dependent. AEs that have been reported are consistent with
side effects known to ERA treatment and included headache,
respiratory AEs, liver enzyme elevations, edema/fluid reten-
tion, and anemia/decrease in hemoglobin. As all ERAs, maci-
tentan is also associated with teratogenicity and therefore
adequate methods of contraception should be used. Although
macitentan should theoretically not affect the efficacy of hor-
monal contraceptives, the lack of clinical PK data requires
that, in addition to a hormonal method, a barrier method

to changes in liver blood flow that are often consequences of
right heart failure in PAH. The disposition of macitentan
depends on both liver and kidney functions.
The conversion of macitentan to the active metabolite
ACT-132577 is mainly catalyzed by CYP3A4, but a smaller
role is also played by CYP2C8, CYP2C9, and CYP2C19.
The consequences of the latter characteristics are reflected in
the drug’s interaction profile. In the presence of ketoconazole,
a strong CYP3A4 inhibitor, exposure to macitentan is approx-
imately doubled. In contrast to bosentan and ambrisentan,
macitentan, at clinically relevant drug concentrations, is not
a substrate of liver drug transporters, which further diminishes
For personal use only.
should be used. Therefore, more clinical drug--drug interac-
tion studies or more real-world data in PAH patients are
needed to fully assess the absence of drug--drug interactions.
Declaration of interest
Funding to support this study and preparation of this manu-
script was provided by Actelion Pharmaceuticals Ltd. PN Sid-
harta and J Dingemanse are full-time employees at Actelion
Pharmaceuticals Ltd. S Krähenbühl was the investigator of a
clinical pharmacology study investigating the pharmacokinet-

the risk for clinically relevant drug interactions. In addition, at
the concentrations reached with the registered daily dose of
10 mg, macitentan does not affect drugs that are substrates
of CYP3A4. As PAH is a disease in which patients usually
take a plethora of concomitant medications such as hormonal
contraceptives, anticoagulants, PDE-5 inhibitors, and statins,
ics of a tablet and capsule formulation of macitentan that was
funded by Actelion Pharmaceuticals Ltd. The authors have no
other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.

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Affiliation
Patricia N Sidharta†1 PharmD PhD,
Stephan Krähenbühl2,3,4 MD PhD PharmD &
Jasper Dingemanse1 PharmD PhD FCP
†
Author for correspondence
1
Actelion Pharmaceuticals Ltd., Department of
Clinical Pharmacology, Gewerbestrasse 16,
CH-4123 Allschwil, Switzerland
Tel: +41 61 656686;
Fax: +41 61 5656200;
E-mail: patricia.sidharta@actelion.com
2
Professor,
University Hospital Basel, Department of
Clinical Pharmacology, Basel, Switzerland
3
University Hospital Basel, Department of
Toxicology, Basel, Switzerland
4
University Hospital Basel, Department of
Research, Basel, Switzerland
13