Macitentan
Macitentan was first approved by the U.S. Food and Drug Administration (FDA) on Oct 18, 2013, then approved by European Medicine Agency (EMA) on Dec 20, 2013, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Mar 26, 2015. It was developed by Actelion Pharms，and marketed as Opsumit® by Actelion Pharms in the US and EU and by Actelion Pharms and Nippon Shinyaku in JP.
Macitentan is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties. It is Indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment).
Opsumit® is available as film-coated tablet for oral use, containing 10 mg of free Macitentan. The recommended dose is 10 mg orally once daily.
Update Date：2016-03-15
- Drug Name：
- Macitentan
- Research Code：
- ACT-064992
- Trade Name：
- Opsumit®
- MOA：
- Endothelin receptor antagonist (ERA)
- Indication：
- Pulmonary arterial hypertension
- Status：
- Approved
- Company：
- Actelion (Originator) , Nippon Shinyaku
- Sales：
-
$541.5 Million (Y2015);
$196.7 Million (Y2014);
$5.4 Million (Y2013); - ATC Code：
- C02KX04
Update Date：2015-08-27
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-10-18 | Marketing approval | Opsumit | Pulmonary arterial hypertension | Tablet, Film coated | 10 mg | Actelion |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-12-20 | Marketing approval | Opsumit | Pulmonary arterial hypertension | Tablet, Film coated | 10 mg | Actelion | Orphan |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2015-03-26 | Marketing approval | Opsumit | Pulmonary arterial hypertension | Tablet, Film coated | 10 mg | Actelion, Nippon Shinyaku |
Update Date：2015-08-27
|
Molecular Weight | 588.27 | ||||||||||||
| Formula | C19H20Br2N6O4S | |||||||||||||
| CAS No. | 441798-33-0 (Macitentan); | |||||||||||||
| Chemical Name | N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide | |||||||||||||
| Macitentan （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-08-31
Update Date：2015-11-25
1. WO2014155304A1.
Update Date：2016-06-07
Mechanism of Action
Macitentan is an oral active dual endothelin (ET) receptor (ETA and ETB) antagonist characterized by high receptor affinity and a slow receptor dissociation rate.
Macitentan inhibited the binding of 125I-ET-1 to recombinant ETA receptors (mean IC50 = 0.49 ± 0.07 nM) and ETB receptors (mean IC50 = 391 ± 0.07 nM) with slow dissociation (T1/2 = 17 min), and in turn inhibited the effects mediated by these receptors including Ca2+ increase (IC50 = 1 nM) in functional assays.
Macitentan had one active circulating metabolite, ACT-132577, which was 8-fold less potent than macitentan on the ETA receptor and 2-fold less potent on ETB in the inhibition of contraction of isolated rat aorta and trachea.
Macitentan and a major metabolite ACT-373898 were screened at a concentration of 10 μM in a panel of 63 radioligand binding assays and caused less than 50% inhibition in all tested receptors and enzymes.
In Vivo Efficacy
In normal rats:
● Increased plasma ET-1 concentrations: At 3 mg/kg
● No effects on heart rate (HR) or mean arterial blood pressure (MAP) at 10 and 30 mg/kg
In rats models of systemic hypertension:
● In Dahl-S rats:
v Dose-dependently decreased MAP: At 0.1-10 mg/kg
v The duration of action was at least 24 h at ≥3 mg/kg
v A sustained decrease in blood pressure: At 1 mg/kg/day for 3 days
In DOCA-salt rats:
● The maximal MAP decrease: 25 mmHg at 10 mg/kg, with the duration of action at least 24 h
● Macitentan (ED50 = 1 mg/kg) was 10-fold more potent than bosentan (ED50 = 10 mg/kg) for MAP reduction.
● The duration of action with macitentan (10 mg/kg, 40 h) was at least twice as long as with bosentan (100 mg, 20 h) at equally effective dose.
No effect on HR was observed in either Dahl-S or DOCA-salt rats.
In monocrotaline-induced pulmonary hypertension (pH) rats:
● A sustained, dose-dependent decrease in mPAP without affecting systemic blood pressure at doses of 0.3-30 mg/kg
● Dose-dependently inhibited pulmonary vascular remodeling and development of right ventricular hypertrophy at 0.3-100 mg/kg for 4 weeks, and prolonged survival at 30 mg/kg for 6 weeks.
In bleomycin-induced PH associated with pulmonary fibrosis rats:
● Macitentan (100 mg/kg/day for 3 weeks) was superior to bosentan (300 mg/kg/day for 3 weeks) in inhibiting development of right ventricular hypertrophy.
Update Date：2016-06-07
Absorption of Macitentan
Exhibited a non-linear pharmacokinetics in humans, rats and dogs following oral dosing. The increase in Cmax and AUCinf appeared to more than dose-proportional in the dose range of 1 to 100 mg macitentan in humans, but less than dose-proportional in the dose range of 1 to 30 mg/kg macitentan in rats and dogs.
Had a moderate to high oral bioavailability in rats (29%-89%) and a high oral bioavailability in dogs (76%-81%).
Was absorbed slowly in rats (Tmax = 6-16 h) and humans (Tmax = 6-8 h), but rapidly in dogs (Tmax = 2 h).
Showed a half-life of 15 h in humans after oral administration, 1.9-5.1 h in rats and 3.5-4.3 h in dogs after intravenous administration.
Had a low clearance in rats (6.5-8.2 mL/min/kg) and dogs (4.6-5.7 mL/min/kg), compared to liver blood flow, after intravenous administration.
Exhibited an extensive tissue distribution in rats and dogs, with an apparent volume of distribution at 1.2-1.8 L/kg, 0.7-1.2 L/kg, respectively.
Showed a high permeability, with the Papp(A→B) (11-13) × 10-6 cm/s in Caco-2 cell monolayer model.
Distribution of Macitentan
Exhibited high plasma protein binding in humans (99%), mice (99.6%), rats (99.4%) and dogs (99.9%).
Had the Cb:Cp ratio of 0.5 in humans, indicating limited partitioning into red blood cells.
In albino and pigmented male rats after a single oral administration: [6]
● The drug was well absorbed and widely distributed into most tissues.
● The highest radioactivity in all tissues was present at the first sampling point at 8 h and declined steadily thereafter.
● At later sampling times, concentrations in over half of the tissues were above that in plasma.
● At most sampling times, relatively higher concentration levels were observed in the liver, kidneys cortex, plasma, blood, and lungs.
● Quantifiable levels of radioactivity were present in many tissues at day 7, with levels in the kidneys and liver remaining above this limit at day 14 and in the kidney cortex at day 28.
● Radioactivity levels in the uveal tract were only slightly higher in pigmented animals, indicating a minor degree of binding of drug-related material to melanin.
Metabolism of Macitentan
The active metabolite M6 (ACT-132577) and inactive metabolite M5 (ACT-373898) were the only metabolites of macitentan detected in human plasma, and M6 was approximately 71% of total drug exposure in plasma.
Could be metabolized by CYP3A4 and to a minor extend by CYP2C19.
CYP3A4 and CYP2C19 catalyzed M6 formation but CYP3A4 was the main contributor (99%).
Macitentan metabolism in rats and dogs showed large similarities to the pattern observed in man.
Excretion of Macitentan
Was predominantly eliminated in urine in humans, with M323u, M1 and M5 were the significant component in urine.
About 72%-74% and 60% of macitentan were recovered in biliary excretion in bile duct-cannulated (BDC) rats and dogs.
Drug-Drug interaction
Macitentan had weak inhibition on CYP3A4 (IC50 = 24 μM for testosterone, 37 μM for midazolam) and CYP2C8 (IC50 = 21 μM), but moderate inhibition on CYP2C9 (IC50 = 5.6 μM).
ACT-132577 inhibited CYP2C8 (IC50 = 23 μM), 2C9 (IC50 = 31 μM), 2C19 (IC50 = 15 μM) and 3A4 (IC50 = 11 μM for testosterone, 7.3 μM for midazolam).
Macitentan and ACT-132577 induced CYP3A4 in a concentration dependent manner.
Macitentan was neither a substrate nor an inhibitor of the P-gp and MDR-1.
Macitentan and ACT-132577 both inhibited OATP1B1 (IC50 = 6.9 and 21 μM), OATP1B3 (IC50 = 14 and 56 μM), and OATP2B1 (IC50 = 0.8 and 15 μM).
Macitentan and ACT-132577 inhibited human NTCP-mediated uptake of taurocholate with IC50 values of 19 μM and 14 μM, respectively. Human BSEP-mediated efflux of taurocholate was also inhibited by both compounds. The respective IC50 values for macitentan and ACT-132577 were 18 μM and 50 μM.
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral gavage administration of macitentan in mice and rats:
● Mouse MTD: ≥2000 mg/kg
● Rat MTD: ≥2000 mg/kg
Repeated-Dose Toxicity
Repeated-dose oral administration of macitentan in mice (up to 13 weeks), rats (up to 26 weeks), and dogs (up to 39 weeks):
● Studies revealed a pattern of findings remarkably similar to those with other members of this drug class, generally including increased liver weight and centrilobular hypertrophy (all three species), dilation of seminiferous tubules (rats and dogs), hemolysis and bone marrow toxicity (rats and dogs), intimal thickening of coronary arteries (dogs only), as well as increased thyroid weight and thyroid follicular hypertrophy (rats only).
Safety Pharmacology
Macitentan had no effect on a battery of behavioral and physiological variables covering the main central and peripheral nervous system functions or on physiological function of the respiratory system at doses up to 100 mg/kg in rats.
Macitentan and its circulating metabolite M6 had no relevant effect (<20% inhibition) on hERG-mediated K+ currents up to a concentration of 10 μM, which was approximately 2000-fold higher than the unbound plasma concentrations of these two compounds at therapeutic doses in humans.
In vivo, macitentan did not induce changes in ECG variables, including ventricular repolarization, in either guinea pigs or dogs. In dogs, a dose-related decrease in blood pressure was observed, which at 5 and 30 mg/kg was associated with a slight increase in heart rate, considered to represent a compensatory physiological response.
Genotoxicity
Macitentan or its metabolites (M3 and M5) gave no evidence of genotoxic potential.
Reproductive and Developmental Toxicity
Fertility and early embryo development: The NOAEL was 10 mg/kg/day in males, and 250 mg/kg/day in females.
Embryo-fetal development: in rats, the maternal NOAEL was 450 mg/kg/day, while a development NOAEL was not established and lies below 150 mg/kg/day; in rabbits, the maternal NOAEL was 25.0 mg/kg, a development NOAEL was not established due to dose-dependent teratogenic effects.
In the pre- and postnatal development: Increase pup mortality and increase pre- and post-implantation at all dose levels, no NOAEL was established for reproduction parameters neither for F0 dams nor for the F1-generation in rats.
Macitentan was excreted into milk. Concentrations of total radioactivity in milk were generally below those in plasma, with milk-to-plasma ratios ranging from 0.32-0.57 in the first 24 h post-dose, reaching a maximum of 2.0 after 96 h.
Carcinogenicity
Carcinogenicity was assessed in 2-year studies in mice and rats, consistently considered negative.
