Macitentan: First Global Approval

Patel, Trina; McKeage, Kate

doi:10.1007/s40265-013-0156-6

Cited by 45 publications

(38 citation statements)

References 18 publications

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“…Based on the results of these high-quality RCTs, ERA (bosentan, ambrisentan and macitentan), selective PDE-5 inhibitors (sildenafil and tadalafil) and riociguat have been approved for treatment of PAH associated with CTDs 44 47 48. The evidence regarding usage of these drugs specifically in SSc-related PAH is less robust.…”

Section: Resultsmentioning

confidence: 99%

Update of EULAR recommendations for the treatment of systemic sclerosis

et al. 2016

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The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research (EUSTAR) group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement. Compared with the 2009 recommendations, the 2015 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressing SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

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Section: Resultsmentioning

confidence: 99%

Update of EULAR recommendations for the treatment of systemic sclerosis

et al. 2016

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“…[47][48][49] However, macitentan (Opsumit) has been developed as an improved dual ET receptor antagonist that has been recently approved for the treatment of pulmonary arterial hypertension and is also under study for systemic sclerosis-associated digital ulcers. 39,50 In vitro, macitentan has been recently described to reduce the profibrotic response of dermal fibroblasts from systemic sclerosis patients. 51,52 It should be, however, noted that these drugs have shown significant side effects that have so far hampered their use as a general antifibrotic therapy.…”

Section: Discussionmentioning

confidence: 99%

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

Busnadiego

Loureiro-Álvarez

Sandoval

et al. 2015

Journal of the American Society of Nephrology

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In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits lowgrade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-b1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-b1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-b1-blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-b1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-b1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PDassociated dysfunction.

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“…Macitentan is metabolized in the liver by the CYP enzymes CYP3A4 and, to a lesser extent, CYP2C19 [18]. Unlike bosentan, macitentan does not appear to be hepatotoxic, despite their similar chemical structures and affinity for the ET-B receptor.…”

Section: Macitentanmentioning

confidence: 99%

“…Sitaxsentan was withdrawn from the market in 2010 after reports of fatal drug-induced hepatotoxicity emerged [16]. The pharmacodynamics and Table 2 [13,17,18]. Currently, bosentan, ambrisentan, and macitentan are all approved as treatment for patients with Group 1 PAH who are WHO functional class II, III, or IV, and are used in addition to primary therapy with diuretics, oxygen (when indicated), digoxin (in some centers), and anticoagulants (in patients with idiopathic, anorexigen, or heritable PAH) ( Table 3) [19].…”

Section: Introductionmentioning

confidence: 99%

“…From these results, the authors selected only articles that were blinded RCTs that compared monotherapy bosentan, ambrisentan, or macitentan in adult (age over 16 years) patients with Group 1 PAH to either placebo or another form of PAH-specific therapy, and excluded all observational studies, reviews, metaanalyses, comments, editorials, and letters. Additional Table 2 The pharmacodynamics and pharmacokinetics of bosentan, ambrisentan, and macitentan [13,17,18] This review includes the drug-drug interactions that were felt to be most significant for patients with PAH.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension

2015

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Pulmonary arterial hypertension (PAH) is a condition that leads to progressive right heart failure and death unless recognized and treated early. Endothelin, a potent endogenous vasoconstrictor, has been identified as an important mediator of PAH. Endothelin receptor antagonists (ERAs) have been associated with an improvement in exercise capacity and time to clinical worsening in patients with Group 1 PAH, and three different ERAs are currently approved for use in this population: bosentan, ambrisentan, and macitentan. While all three ERAs are generally well-tolerated, they each have important adverse effects that need to be recognized and monitored. In particular, they may cause anemia, peripheral edema, and mild cardiac, respiratory, neurologic, and gastrointestinal adverse effects to varying degrees. Although bosentan increases a patient's risk of developing liver transaminitis, ambrisentan and macitentan do not appear to confer the same risk of hepatotoxicity at this time. Important drug-drug interactions, particularly involving other drugs metabolized via the cytochrome P450 pathway, are important to recognize when prescribing ERAs. In this review, we provide a brief overview of the current state of knowledge as it relates to the adverse effect profiles, tolerability, and drug-drug interactions of this class of medication as informed by the results of randomized clinical trials, drug surveillance programs, and regulatory agencies.

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Macitentan: First Global Approval

Cited by 45 publications

References 18 publications

Update of EULAR recommendations for the treatment of systemic sclerosis

Update of EULAR recommendations for the treatment of systemic sclerosis

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension

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