Macitentan
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| Non-proprietary name | Macitentan | |||||||||||||||
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| Molecular formula | C 19 H 20 Br 2 N 6 O 4 S | |||||||||||||||
| Brief description |
beige-white powder |
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| Mechanism of action |
Dual endothelin receptor antagonist |
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| Molar mass | 588.37 g · mol -1 | |||||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||
Macitentan (trade name Opsumit ; manufacturer Actelion Pharmaceuticals Ltd ) is a drug from the group of dual endothelin receptor antagonists (ERA). It is used in the treatment of high blood pressure in the pulmonary circulation ( pulmonary arterial hypertension ).
Clinical information
Application areas (indications)
Macitentan is a novel dual endothelin receptor antagonist (ERA) with good tissue penetration and the property of being able to bind to receptors for a long time. Macitentan was developed by the Swiss company Actelion Pharmaceuticals for the treatment of pulmonary arterial hypertension (PAH). Further indication areas are currently being researched. Pathophysiologically, PAH is based on changes in the pulmonary vessels. Endothelin-1 (ET-1), which is mainly secreted into the tissue by the endothelial cells , plays a key role in this process.
Macitentan was approved in Germany on January 20, 2013. The US agency FDA granted approval for the active ingredient in October 2013. In preclinical studies it has been shown that macitentan inhibits the binding of ET-1 to the ET receptors in various cell systems, organs and animal models. It was possible to demonstrate greater effectiveness for macitentan than for bosentan and ambrisentan , two endothelin receptor inhibitors that have been approved for a long time. On this basis, macitentan was further investigated in clinical trials for the treatment of PAH.
The efficacy and safety of macitentan in PAH was investigated in the SERAPHIN study (SERAPHIN = Study with Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to improve clinical outcome). SERAPHIN is an event-driven long-term study with the combined endpoint morbidity / mortality. With 742 participants and a study duration of 3.5 years, SERAPHIN is the largest and longest completed PAH study to date, for which a prognostically relevant and robust primary study endpoint was defined for the first time: the time until the occurrence of the first morbidity / mortality event . The study participants were randomized in a ratio of 1: 1: 1 and received either 3 mg macitentan, 10 mg macitentan or placebo once daily . PAH-specific concomitant medications were allowed, and around two thirds of the patients were already taking other PAH-specific medications, primarily phosphodiesterase -5 inhibitors such as B. Sildenafil a.
The result showed:
- Macitentan in the EMA and FDA approved dosage of 10 mg significantly reduces the risk of a morbidity / mortality event by 45%. The risk reduction could be clearly shown for therapy-naive patients as well as for patients with PAH-specific previous therapy.
- Macitentan has a significantly positive effect on the hospitalization rate (secondary endpoint): Macitentan therapy at a dose of 10 mg reduced the risk of hospitalization compared to placebo by about 50 percent (p <0.001).
- Macitentan was well tolerated in the SERAPHIN study; side effects such as increased liver function tests and increased edema rates were no more common than in the placebo group. Compared to the control group, macitentan-treated patients had higher incidence of nasopharyngitis , headache, and anemia . One patient from each group, including the placebo group, discontinued treatment due to anemia.
Type and duration of application
The active ingredient is administered orally. In the phase III clinical study, doses of 3 mg and 10 mg once a day were used. It is available in a dosage of 10 mg per tablet, which is also the maximum dosage.
Drug interactions
Since the active substance is metabolized via the liver enzymes of the type CYP3A4 , drugs that induce or inhibit this enzyme should not be used at the same time. However, macitentan itself has no enzyme-inducing or -inhibiting effects.
Use during pregnancy and breastfeeding
The active ingredient is contraindicated in pregnancy as it can damage the development of the fetus. A negative pregnancy test is therefore required before and one month after the start of treatment, followed by permanent contraception measures.
Adverse effects (side effects)
Macitentan has no influence on the bile salt export pump . As a result, macitentan does not seem to lead to an increase in liver values, which can occur as an undesirable effect with other endothelin receptor antagonists. Macitentan has demonstrated a good drug interaction profile in vitro and in vivo . In the clinical trials of Opsumit®, the most common side effects were anemia, upper respiratory tract infections, bronchitis, headache, influenza and urinary tract infections. The use of other ERAs has also been associated with increases in aminotransaminases , hepatotoxicity and liver failure. Therefore liver enzyme tests should be carried out during treatment with Opsumit® and the treatment should be discontinued if liver failure sets in. An inhibition of spermatogenesis was also observed in the case of substances with a related effect . The anemia and lowering of hematocrit , which are also associated with other active substances in this group of drugs, were also observed in the clinical studies of Opsumit . However, they appeared early and stabilized over the course of treatment, and a transfusion was rarely necessary. Therefore, patients with severe anemia are not advised to use the drug.
Early benefit assessment according to § 35a SGB V
As for exceeding the 50-million € sales mark for orphan drugs in the pharmaceutical market Restructuring Act provided that has IQWiG presented in 2017 a dossier evaluation. Accordingly, an additional benefit compared to the ACT specified by the Federal Joint Committee (G-BA) has not been proven. The Federal Joint Committee (G-BA) endorsed the assessment result.
Pharmacological properties
Mechanism of action (pharmacodynamics)
As a dual endothelin receptor antagonist, macitentan blocks both ET A and ET B receptors. The main natural ligand of these receptors is endothelin -1, which acts as a powerful vasoconstrictor . Blocking these G q protein-coupled receptors prevents the influx of Ca 2+ into the smooth muscle cells and thus prevents the vasoconstriction of the blood vessels in the pulmonary circulation. This leads to a decrease in vascular resistance, which in turn indirectly leads to a decrease in blood pressure.
Absorption and distribution in the body (pharmacokinetics)
Macitentan is converted into its active metabolite ACT-132577 by oxidative depropylation . Both substances are excreted in the form of their hydrolysis products, 2/3 in the urine and 1/3 in the faeces . Despite its insolubility in water, macitentan can be transported well in the blood as it has a plasma protein binding of over 99%. The messenger substance endothelin , a protein found in the endothelium, plays a key role in the pathogenesis of PAH . Endothelin is one of the most powerful known endogenous vasoconstrictors (100 times higher vasoconstrictor potency than norepinephrine, 10 times higher than angiotensin II). In patients with PAH, there are increased plasma concentrations of endothelin, which correlate with the severity of the disease. An increased concentration is associated with an increased mortality. The harmful endothelin effects are mediated via two different receptor subtypes (ETA and ETB), the expression and distribution pattern of which can be changed under pathophysiological conditions and lead to the compensatory takeover of the other receptor subtype (" receptor crosstalk "). As an antagonist, macitentan displaces endothelin-1 and thus counteracts the damaging ET-1 effects - vasoconstriction, inflammation and remodeling of the pulmonary vessels.
Long-lasting receptor binding
The pharmacological activity and ultimately the clinical efficacy of receptor antagonists such as macitentan can be influenced in vivo by the binding kinetics. The association and dissociation rates of macitentan with regard to the ET receptor were examined in vitro and compared with bosentan and ambrisentan . As a result, macitentan showed an increased affinity for the ET receptors in comparison to the already approved endothelin receptor antagonists, a long-lasting receptor binding and lasting pharmacological activity.
Improved tissue penetration
Macitentan shows optimized physico-chemical properties. The macitentan molecule, for example, has a high non-ionized content, which makes it possible to penetrate lipophilic cell membranes better and faster. As a result, the tissue penetration of macitentan could be increased so that its effect can be used precisely where it is needed - in the tissue of the pulmonary vessels.
toxicology
Macitentan was tested orally for carcinogenicity in mice of both sexes at 75 to 140 times the dose used in humans and in rats of both sexes at 8.3 to 42 times the dose. No carcinogenic effects could be determined here.
The tests were also similar in the area of mutagenicity. Tests were carried out on the standard battery. For this purpose, in vitro and in vivo tests, bacterial reverse mutation tests, a test for gene mutations in mouse lymphoma cells , a chromosome aberration test in human lymphocytes and an in vivo micro-nucleus test in rats were carried out.
Treatments of juvenile rats at postnatal days 4 to 114 resulted in decreased body weight gain and testicular tubular atrophy at exposures 7 times that of human. In chronic toxicity studies at exposures greater than 7 and 23 times the human dose in rats and dogs, reversible tubular dilation was observed in the testis area.
After 2 years of treatment, tubular atrophy was also seen in rats exposed to 4 times the human dose over this period. Macitentan did not affect male or female fertility in the range of 19 to 44 times human exposure. It also had no effect on sperm count, motility or morphology in male rats. No changes in the testes were seen in mice after two years of treatment. Again, fertility was not affected.
Reduced blood pressure has been observed in dogs when treated with macitentan. The animals were treated with approximately the same dose as humans. At 17 times the human exposure, coronary artery intima thickening occurred after 4–39 weeks of treatment. However, due to the species-specific sensitivity and the dose difference compared to use in humans, this finding is not considered relevant for humans.
In long-term studies in mice, rats and dogs treated with 12 to 116 times the dose, there were no findings that indicate damage to the liver after long-term therapy.
There are no data in the literature on a dose that caused death in the test animals with macitentan.
chemistry
synthesis
The synthesis begins with the reaction of chlorosulfonyl isocyanate ( 1 ) tert -butanol . This creates a BOC- protected aminosulfonyl chloride ( 2 ). With n- propylamine , a BOC-protected sulfamide ( 3 ) is formed with elimination of hydrochloric acid . The BOC protective group is split off and the sulfamide ( 4 ) formed is converted into the potassium salt ( 5 ) using potassium tert- butanolate . Potassium tert -butanolate acts here as a very strong base for deprotonation. This potassium sulfamide salt reacts with the nucleophilic substituent on the heteroaromatic of the dichloropyrimidine derivative ( 6 ) with elimination of KCl to form a monochloropyrimidine intermediate ( 7 ). The ethylene glycol side chain is generated by adding ethylene glycol ( 8 ). With 2-chloro-5-bromopyrimidine, macitentan ( 9 ) is formed in an S N 1 reaction with elimination of HCl .
properties
Macitentan has a basic center, which can also be used for reactivity analysis. This is located on the nitrogen atom of the pyrimidine ring facing away from the sulfone group . This nitrogen can easily be protonated and thus receives a positive charge.
Identity check and determination of salary
For a qualitative analysis, for example, a Beilstein test for organic halogen compounds would be possible, in which the two bromine atoms on the peripheral rings are detected. Alternatively, after previous Lassaigne digestion , the halogens could also be precipitated as silver bromide by elemental analysis and, for example, determined gravimetrically .
See also
Trade names
- Opsumit
Individual evidence
- ↑ Lancrix Chemicals: Macitentan | CAS number: 441798-33-0 | Lancrix Chemicals , accessed Sunday March 2, 2014.
- ↑ a b c d Martin H. Bolli, Christoph Boss, Christoph Binkert, Stephan Buchmann, Daniel Bur, Patrick Hess, Marc Iglarz, Solange Meyer, Josiane Rein, Markus Rey, Alexanderreiber, Martine Clozel, Walter Fischli, Thomas Weller: The Discovery of N- [5- (4-bromophenyl) -6- [2 - [(5-bromo-2-pyrimidinyl) oxy] ethoxy] -4-pyrimidinyl] -N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist. In: Journal of Medicinal Chemistry. 55, 2012, pp. 7849-7861, doi : 10.1021 / jm3009103 .
- ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
- ↑ Patent application WO2002053557 : Novel sulfamides and their use as endothelin receptor antagonists. Filed on December 18, 2000 , published on July 11, 2002 , Applicant: Actelion, inventor Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli et al
- ↑ Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 809-18.
- ↑ a b c d Actelion website: macitentan ( Memento of the original from January 13, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , accessed on Thursday, January 9, 2014.
- ↑ IQWiG reports - No. 476 Macitentan (pulmonary arterial hypertension) - benefit assessment according to Section 35a SGB V , accessed on August 20, 2018.
- ↑ Resolution of the Federal Joint Committee of April 6, 2017 on an amendment to the Drugs Directive (AM-RL): Annex XII - Macitentan (reassessment of an orphan drug after exceeding the 50 million euro limit) , accessed on August 20, 2018.
- ↑ a b c d U.S. National Library of Medicine (NLM): OPSUMIT (macitentan) tablet, section-12.2 , accessed Thursday, January 9, 2014.
- ↑ Distribution in the body according to informahealthcare.com: Shirin Bruderer, Gerard Hopfgartner, Michael Seiberling, Janine Wank, Patricia N. Sidharta, Alexanderreiber, Jasper Dingemanse: Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. In: Xenobiotica. 42, 2012, pp. 901-910, doi : 10.3109 / 00498254.2012.664665 , accessed on Thursday, January 9, 2014.
- ↑ Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O (2012). Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells. PLOS ONE 7 (10): e47662. doi : 10.1371 / journal.pone.0047662 .
- ↑ Iglarz M et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J PharmacolExpTher. 2008; 327 (3): 736-745.
- ↑ Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J ClinPharmacol. 2011; 67 (10): 977-984.
- ↑ Bruderer S et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans.Xenobiotica. 2012 Sep; 42 (9): 901-910.
- ↑ Bruderer S et al. Effect of cyclosporine A and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012; 14 (1): 68-78.
