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Macitentan
1. Macitentan
A Review of Its Use in Patients with Pulmonary
Arterial Hypertension
Rupendra KUMAR Bharti
1st year Post Graduate
student
Deptt. of Pharmacology
on april 18th
Drugs (2014) 74:1495–1507
DOI 10.1007/s40265-014-0266-9
1
2. Introduction
Pulmonary arterial hypertension (PAH) is a chronic and
progressive disease characterized by the presence of pre
capillary pulmonary hypertension (PH; defined as pulmonary
arterial pressure of > 25 mmHg, pulmonary wedge pressure of <
15 mmHg, and normal or reduced cardiac output) in the absence
of other causes of pre-capillary PH (e.g. lung diseases or chronic
thromboembolic PH).
2
3. PAH can be classified according to its underlying aetiology
and severity.
The disease results from functional and structural changes in
the pulmonary vasculature, leading to increased pulmonary
vascular resistance, right ventricular failure and subsequently
death.
3
4. Imbalances in three main biological pathways, the
prostacyclin, nitric oxide and endothelin (ET)-1
pathways, have been implicated in the pathogenesis of
PAH.
Current treatment strategies target these pathways and
help to re-establish the equilibrium between
vasoconstriction and vasodilation, and control abnormal
proliferation.
4
5. Increased levels of ET-1 have been seen in the plasma and
pulmonary vascular endothelium of patients with PH,
indicating that ET-1 is likely to contribute to the vasodilator/
vasoconstrictor imbalance associated with PAH.
ET-1 is released mainly from the basal surface of the
endothelium and acts largely on the underlying smooth
muscle cells, resulting in vasoconstriction and proliferation.
5
6. In addition, ET-1 acts on the endothelium to induce
proliferation, vasodilation and vasoconstriction, and on
the fibroblasts to stimulate contraction, proliferation and
fibrosis.
ET-1 mediates its effects via two receptor subtypes, the
ETA receptors (expressed on smooth muscle cells,
fibroblasts and cardiac myocytes) and the ETB receptors
(expressed predominantly on endothelial cells and to a
lesser extent on vascular smooth muscle cells,
fibroblasts and macrophages).
6
7. Endothelin receptor antagonists (ERAs), along with
prostanoids (targeting the prostacyclin pathway) and
phosphodiesterase-5 (PDE5) inhibitors (targeting the
nitric oxide pathway), are the mainstay of current
treatment strategies for PAH.
Macitentan is a potent, dual ETA /ETB ERA, which
was recently approved for the treatment of PAH.
This article reviews the pharmacological properties,
efficacy and tolerability data relevant to the use of
macitentan in this indication.
7
8. WHO classification of functional status of patients with pulmonary
hypertension (modified from the New York Heart Association functional
classification)
Class Description
I Patients with pulmonary hypertension but without resulting
limitation of physical activity.
Ordinary physical activity does not cause undue dyspnoea or
fatigue, chest pain, or near syncope
II Patients with pulmonary hypertension resulting in slight
limitation of physical activity.
They are comfortable at rest. Ordinary physical activity causes
undue dyspnoea or fatigue, chest pain, or near syncope.
8
9. CLASS DESCRIPTION
III Patients with pulmonary hypertension resulting
in marked limitation of physical activity.
They are comfortable at rest. Less than ordinary
physical activity causes undue dyspnoea or fatigue,
chest pain, or near syncope.
IV Patients with pulmonary hypertension with inability to
carry out any physical activity without symptoms.
These patients manifest signs of right heart failure.
Dyspnoea and/or fatigue may even be present at rest.
Discomfort is increased by any physical activity
9
10. SIGN/SYMPTOMS
M/C symptom- dyspnoea
Fatigue
Cough (no productive)
Fainting/ syncope
Angina
Peripheral Oedema (swelling around the ankles
and feet)
Haemoptysis (rare)
Pulmonary venous hypertension typically presents
with shortness of breath while lying flat or sleeping
(orthopnea or paroxysmal nocturnal dyspnea),
while pulmonary arterial hypertension (PAH)
typically does not.
Pedal edema
Ascites
Raise Hepatojugular
reflux
Clubbing
11. Diagnosis
• Pulmonary function tests
• Blood tests to exclude HIV, autoimmune diseases,and liver disease.
• Electrocardiography (ECG)
• Arterial blood gas measurements
• X-rays of the chest (followed by high-resolution CT scanning if
interstitial lung disease is suspected)
• Ventilation-perfusion or V/Q scanning to exclude chronic
thromboembolic pulmonary hypertension.
• Echocardiography: for predicting right heart catheterisation
reported a sensitivity and specificity of 88% and 56%, respectively.
12. Indication
As monotherapy or in combination, for the long-term treatment of
pulmonary arterial hypertension (PAH) in adult patients of WHO
Functional Class (FC) II to III.
Dosing Information
10mg once daily, with or without food. The film-coated tablets are
not breakable and are to be swallowed whole with water.
Macitentan should be taken every day at about the same time.
Product availability date
13 January 2014. Macitentan was designated as a orphan
medicinal product in September 20111
12
13. Pharmacodynamic Properties
Macitentan is a potent inhibitor of ETA receptors (half
maximal inhibitory concentration [IC50] of 0.5 nmol/L in an in
vitro assay) with significant affinity for ETB receptors (IC50
391 nmol/L).
Its ETA/ETB inhibitory potency ratio was 50:1 in functional
assays in isolated organs.
The major metabolite of macitentan ACT-132577 is also
pharmacologically active at these receptors (ETA/ETB
inhibitory potency ratio was 16:1) and is ≈20 % as potent as
the parent compound.
13
14. Macitentan displayed slower receptor dissociation kinetics
than ambrisentan and bosentan (receptor occupancy half-life
of ≈17 min vs. ≈40 and ≈70sec) and, unlike ambrisentan and
bosentan, blocked ET-1 receptor activation across a wide
range of ET-1 concentrations, suggesting a more complete
block of ET-1 binding under conditions of locally fluctuating
ET-1 levels.
14
15. Pharmacodynamic effects of macitentan relevant
to pulmonary arterial hypertension
In vitro and animal studies
Macitentan and its major metabolite (ACT-132577)
inhibited ET-1-mediated deleterious effects in in vitro
functional assays (e.g. inhibited ETA receptor-mediated
contraction of isolated rat aorta and ETB receptor-mediated
contraction of isolated rat trachea).
Chronic administration of macitentan prevented the
development of PH and right ventricle hypertrophy at a 10-
times lower dose than bosentan in a rat model of PH;
survival was also improved with macitentan in this model.
15
16. Macitentan attenuated the progression of PH with angio-
proliferative occlusive lesions in a rat model of PAH,
suggesting that its beneficial effects on PH may be
mediated by preventing arteriopathy.
Like bosentan, macitentan dose-dependently increased
mean arterial BP, but did not affect heart rate in
hypertensive rats.
16
17. Human studies
Dose-dependently decreased plasma ET-l levels in
healthy volunteers; at steady state (day 10), the
maximum effect on ET-1 levels (twofold increase from
baseline) was seen with a macitentan dosage of 10
mg/day.
Generally did not affect serum total bile salt levels in
healthy volunteers, suggesting an improved safety
profile compared with other ET-1 receptor antagonists.
17
18. Macitentan 10 mg od for a median of 115 months delayed
disease progression in patients with PAH.
There was no evidence of prolonged cardiac repolarization
or other ECG changes with therapeutic (10 mg od) or
supra-therapeutic dosages (30 mg od) of macitentan in
healthy volunteers in a thorough corrected QT study in
healthy volunteers.
18
19. ADME
The estimated oral bioavailability of macitentan is 74 %.
Macitentan and ACT-132577 are highly plasma protein
bound (99 %), largely to albumin and to a lesser extent to
∝1-acid glycoprotein; both the parent compound and the
active metabolite poorly bind to and penetrate into
erythrocytes.
Macitentan and ACT-132577 are well distributed into
tissues, with apparent volumes of distribution of 40-50%, in
healthy volunteers.
19
20. Macitentan is metabolised largely by oxidative
depropylation of the sulfamide to its metabolite ACT-
132577, with the reaction mediated primarily (≈ 99 %) by
cytochrome P450 (CYP) 3A4 and minor contributions by
CYP2C8, CYP2C9 and CYP2C19.
Macitentan is excreted largely via the kidneys, with & 50 %
of a radio-labelled dose recovered in the urine (none in the
form of unchanged drug or as ACT-132577) and 24 % of the
dose recovered in the faeces.
The apparent elimination half-life of macitentan was ≈ 16 h
and that of ACT-132577 was ≈ 48 h.
20
21. Special Populations
Age, sex and ethnicity do not affect the pharmacokinetics of
macitentan and ACT-132577 to a clinically relevant extent.
There were no clinically relevant differences in the
pharmacokinetics of macitentan between Caucasian and
Japanese healthy volunteers.
The effects of severe renal impairment (creatinine clearance 15–
29 mL/min) and mild, moderate or severe hepatic impairment
(Child-Pugh class A, B and C) on the pharmacokinetics of
macitentan and ACT-132577 were not considered clinically
relevant, according to pharmacokinetic data in patients who did
not have PAH and, therefore, no dosage adjustment is required
21
22. However, no studies have evaluated the pharmacokinetics of
macitentan in patients with PAH who have moderate or
severe hepatic impairment or severe renal impairment.
Consequently, in the EU, its use is contraindicated in patients
with PAH who have severe hepatic impairment (with or
without cirrhosis) and in patients with alanine
aminotransferase (ALT) or aspartate aminotransferase ≥3
times the upper limit of normal (ULN) at baseline;
macitentan is also not recommended in patients with PAH
and moderate hepatic impairment and in patients undergoing
dialysis.
22
23. Potential Drug Interactions
In in vitro studies, macitentan and ACT-132577 did not have
clinically relevant inhibitory or inducing effects on CYP enzymes.
Macitentan and ACT-132577 also did not inhibit hepatic or renal
transporters [including organic anion transporting polypeptide
(OATP) 1B1 and OATP1B3], and hepatic or renal efflux pumps
[including P-glycoprotein (P-gp)/multidrug resistance protein-1
(MDR-1), and multidrug and toxin extrusion transporters 1 and
2K], and did not interact with proteins involved in hepatic bile
transport [i.e. bile salt export pump (BSEP) and the sodium-
dependent taurocholate co-transporting polypeptide (NTCP)] at
clinically relevant concentrations.
23
24. Studies in healthy volunteers showed that the concomitant use
of macitentan with strong CYP3A4 inhibitors (e.g.
ketoconazole) approximately doubles the exposure to
macitentan ; therefore, the concomitant use of macitentan and
strong CYP3A4 inhibitors (e.g. antiretroviral drugs such as
ritonavir) should be avoided or caution should be exercised
when these agents are coadministered.
Strong inducers of CYP3A4 [e.g. rifampicin (rifampin)]
significantly reduce macitentan exposure when coadministered ;
consequently, coadministration of macitentan with these agents
should be avoided.
24
25. The pharmacokinetics of macitentan and sildenafil were
not altered to a clinically relevant extent when the two
drugs were used concomitantly in healthy volunteers;
therefore, no dosage adjustment is required.
Macitentan administered concomitantly with warfarin
did not alter the pharmacodynamic effect of warfarin on
the international normalised ratio in healthy volunteers.
Coadministration of macitentan with cyclosporine A
(CYP3A4 and OATP inhibitor) in healthy volunteers did
not alter the steady state exposure to macitentan.
25
26. Therapeutic Efficacy
The efficacy of oral macitentan was evaluated in the
randomized, double-blind, multi-centre, placebo-
controlled, event-driven SERAPHIN study (Study with
an Endothelin Receptor Antagonist in Pulmonary
Arterial Hypertension to Improve Clinical Outcome).
The SERAPHIN study included patients aged >12 years
who had idiopathic or heritable PAH, or PAH related to
connective-tissue disease, repaired congenital systemic-
to-pulmonary shunts, HIV infection or drug use/toxin.
26
27. Patients were required to have a confirmed diagnosis of
PAH (using right heart catheterization), a 6-min walk
distance of > 50 m and WHO functional class II–IV
disease.
Patients were eligible regardless of whether they were
receiving background therapy for PAH; concomitant
treatment with stable-dose oral PDE5 inhibitors, oral or
inhaled prostanoids, calcium-channel antagonists or L -
arginine was permitted. Exclusion criteria included
treatment with intravenous or subcutaneous prostanoids.
27
28. Patients (n = 742) were randomized to receive macitentan 3 or
10 mg once daily or placebo until study end, which was
declared when a predefined number (n = 285) of events had
occurred.
The mean duration of double-blind treatment in the macitentan
3 and 10 mg groups and the placebo group was 99.5, 103.9 and
85.3 weeks, respectively.
The composite primary endpoint was the time from the
initiation of therapy to the occurrence of the first PAH related
event (i.e. worsening of PAH, initiation of treatment with
intravenous or subcutaneous prostanoids, lung transplantation
or atrial septostomy) or death from any cause up to the end of
treatment.
28
29. At baseline, the mean age of patients was & 46 years, the mean
duration of disease was 2.7 years and ≈77 % of patients were
female.
Patients had idiopathic (55 %) or heritable (2 %) PAH, or PAH
associated with connective- tissue disorders (31 %), congenital
shunts (8 %), drug use/toxin exposure (3 %) or HIV infection
(1 %).
Approximately 52, 46 and 2 % of patients were in WHO
functional class II, III and IV, respectively.
Sixty-four percent of patients were receiving background
therapy for PAH (61 % PDE5 inhibitors and 5 % oral or
inhaled prostanoids); 51 % of patients were receiving
anticoagulant therapy.
29
30. Morbidity and Mortality
Macitentan 10 mg once daily was effective in delaying
disease progression in patients with PAH.
Over a median double-blind treatment duration of 115
weeks (up to a maximum of 188 weeks of macitentan),
macitentan significantly reduced mortality and morbidity
relative to placebo, as indicated by a 45 % (P <0.001)
reduction in the risk of experiencing a primary composite
endpoint event, with the treatment effect largely
attributable to a reduction in clinical worsening events.
30
31. Kaplan-Meier Estimates of the Occurrence of the Primary
Endpoint Event in the SERAPHIN Study (OPSIUM=
MECITENTAN)
31
32. Placebo N=250
n (%)
MACIMENTAN 10
mg N=242 n (%)
Patients with a
primary endpoint
event
116 (46.4) 76 (31.4)
Component as first event
Worsening PAH
Death
IV/SC prostanoid
93 (37.2)
17 (6.8)
6 (2.4)
59 (24.4)
16 (6.6)
1 (0.4)
Summary of Primary Endpoint Events
32
33. Macitentan treatment also significantly reduced the risk of
PAH-related death or hospitalization (secondary composite
endpoint event) by 50 % relative to placebo, with a
reduction in the rate of hospitalization accounting for the
majority of the treatment effect.
Other outcomes, including the incidences of all-cause
death and death because of PAH did not differ
significantly between macitentan and placebo
recipients.
The lack of a significant treatment effect in terms of
mortality outcomes is not unexpected, as PAH is a
progressive disease and clinical deterioration is likely to
precede death
33
34. Kaplan-Meier Estimates of the Occurrence of Death due to PAH or Hospitalization
for PAH in SERAPHIN (OPSIUM= MECITENTAN)
34
35. Summary of Death due to PAH and Hospitalization due to PAH
Placebo N=250
n (%)
MACIMENTAN 10
mg N=242 n (%)
Death due to PAH or
hospitalization for
PAH
84 (33.6) 50 (20.7)
Component as first event
Death due to PAH
Hospitalization for PAH
5 (2.0)
79 (31.6)
5 (2.1)
45 (18.6)
35
36. Symptomatic Endpoints and Health-Related
Quality of Life
At 6 months, macitentan 10 mg once daily significantly improved the 6-
min walk distance by 22 m relative to placebo, with significant
improvements seen by month 3 and maintained for the duration of the
study.
WHO functional class improved from baseline to month 6 in significantly
(p = 0.006) more macitentan than placebo recipients (22% vs. 13
%),which translates to a 74 % higher chance of experiencing
improvement in this outcome.
Macitentan recipients had significant improvements in the SF-36
physical and mental component summary scores after 6 month of
treatment.
36
37. Haemodynamic Endpoints
A haemodynamic sub-study of SERAPHIN involving
patients who had right heart catheterisation at baseline and
month 6 (n = 145 evaluable) showed that macitentan
10 mg once daily treatment significantly reduced
pulmonary vascular resistance (38.5 % decrease in the
fold-change from baseline) and significantly increased
cardiac index (by 0.63 L/min/m2 ) at 6 months relative to
placebo, with the benefit of treatment seen regardless of
background PAH therapy or WHO functional class at
baseline.
37
39. Dosage and Administration
In the EU, oral macitentan as monotherapy or combination therapy
is indicated for the long-term treatment of PAH in adults of WHO
functional class II or III.
In the USA, oral macitentan is indicated for the treatment of PAH
(WHO group I) to delay disease progression and reduce
hospitalization for PAH.
The recommended dosage of oral macitentan is 10 mg once daily,
with or without food.
39
40. The use of macitentan may be associated with elevations of
liver aminotransferase (ALT or AST) and a decrease in
haemoglobin levels; therefore, patients should be monitored
prior to and during treatment as clinically indicated.
No dosage adjustment is required in elderly patients aged
>65 years; however, caution is advised in patients aged >75
years, as data are limited in these patients.
As macitentan may cause foetal harm, its use is
contraindicated in pregnant or breast feeding women and in
women of child bearing potential who are not using reliable
contraception
40
