Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension

Iglarz, Marc; Bossu, Alexandre; Wanner, Daniel; Bortolamiol, Céline; Rey, Markus; Hess, Patrick; Clozel, Martine

doi:10.1016/j.lfs.2014.02.018

Cited by 38 publications

(30 citation statements)

References 15 publications

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“…16,17 In addition, it has been recently reported that acute administration with 30 mg/kg of macitentan further lowered pulmonary arterial pressure in monocrotaline-exposed rats with the maximal dose of bosentan (100 mg/kg). 18 We therefore hypothesized that efficacious blockade of ET receptors by macitentan could chronically reverse severe PAH in a preclinical model of occlusive PAH without major side effects including liver dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Novel Dual Endothelin Receptor Antagonist Macitentan Reverses Severe Pulmonary Arterial Hypertension in Rats

Kunita-Takanezawa¹,

Abe

Hirooka

et al. 2014

Journal of Cardiovascular Pharmacology

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The efficacy of endothelin (ET) receptor antagonist bosentan in patients with severe pulmonary arterial hypertension (PAH) remains limited, partly because its higher doses for potential blockade of ET receptors have never been tested due to liver dysfunction. We hypothesized that rigorous blockade of ET receptors using the novel dual ET receptor antagonist macitentan would be effective in treating severe PAH without major side effects in a preclinical model appropriately representing the human disorder. In normal rats, 30 mg·kg·d of macitentan completely abolished big ET-1-induced increases in right ventricle (RV) systolic pressure. Adult male rats were injected with SU5416, a vascular endothelial growth factor blocker, and exposed to hypoxia for 3 weeks and then to normoxia for an additional 5 weeks (total 8 weeks). In intrapulmonary arterial rings isolated from rats with severe PAH, macitentan concentration dependently inhibited ET-1-induced contraction. Long-term treatment with macitentan (30 mg·kg·d, from week 3 to 8) reversed the high RV systolic pressure with preserved cardiac output. Development of RV hypertrophy, luminal occlusive lesions and medial wall thickening were also significantly improved without increasing serum levels of liver enzymes by macitentan. In conclusion, efficacious blockade of ET receptors with macitentan would reverse severe PAH without major adverse effects.

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Section: Introductionmentioning

confidence: 99%

Novel Dual Endothelin Receptor Antagonist Macitentan Reverses Severe Pulmonary Arterial Hypertension in Rats

Kunita-Takanezawa¹,

Abe

Hirooka

et al. 2014

Journal of Cardiovascular Pharmacology

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“…22 In addition, adding macitentan when the maximum bosentan effect had been reached further decreased mean pulmonary arterial pressure in bleomycin-treated rats, whereas no further reduction in mean pulmonary arterial pressure was seen when bosentan was added after the maximum macitentan effect had been reached. 23 In human studies, in SERAPHIN, the addition of macitentan had a beneficial effect in the subgroup of patients already receiving background pulmonary arterial hypertension therapy. 9 According to our results, switch from bosentan to macitentan improved exercise capacity in children and young adults with pulmonary arterial hypertension significantly in the first 6 months, but not incrementally thereafter and well tolerated without any adverse events in the long term.…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension: extended study results

et al. 2020

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Background:Macitentan is an orally active, potent, dual endothelin receptor antagonist and is the only registered treatment for pulmonary arterial hypertension that significantly reduced morbidity and mortality in a long-term study.Aim:We have recently reported that switch from bosentan to macitentan significantly improved exercise capacity in children and young adults with pulmonary arterial hypertension in a 24-week prospective study and well tolerated without adverse events. We now aimed to evaluate clinical efficacy, safety of switch in a larger patient population, in a 24-month prospective study.Methods:This is a single-institution, 24-month prospective study. Patients ≥12 years with idiopathic/heritable, pulmonary arterial hypertension, or related to CHD or residual pulmonary arterial hypertension due to repaired congenital systemic-to-pulmonary shunts and on bosentan treatment were included. Concomitant treatment with oral phosphodiesterase type 5 inhibitors/inhaled prostanoids was allowed. Outcome measures included change from baseline to 24 months, in the 6-minute walk distance, functional class, oxygen saturation at rest/after walk distance test, and natriuretic peptide levels. Safety end points included adverse events, laboratory abnormalities.Results:Twenty-seven patients (19 adults/8 children, mean age: 21.1 ± 6.3 years (12–36), weight: 53.1 ± 15.7 kgs (26–87)) were included. Mean duration of macitentan treatment: 22.3 ± 3.9 months (9–24). Six-minute walk distance significantly improved from baseline (mean: 458 ± 79 m (300–620)) at 6 months (mean: 501 ± 73 m (325–616) + 43 m) (p < 0.05), at 12 months (mean: 514 ± 82 m (330–626) + 56 m) (p < 0.05), and at 24 months (mean: 532 ± 85 m (330–682) + 74 m) (p < 0.05). We observed a significant improvement during the first 6 months but no incremental improvement after 6 months (p > 0.05). Macitentan did not significantly change functional class, oxygen saturation, and natriuretic levels (p > 0.05). None of the patients had anaemia, hepatotoxicity, and peripheral edema.Conclusions:Our study is the first study which showed that switch from bosentan to macitentan improved exercise capacity in children and young adults with pulmonary arterial hypertension significantly in the first 6 months and compared to baseline in 24 months and well tolerated without adverse events.

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“…In the Dahl salt‐sensitive rat model, the ability of macitentan to produce a superior blockade of ET receptors relative to other ERAs was confirmed. Macitentan had an additive effect on lowering MAP in bosentan‐treated animals, demonstrating macitentan's relatively higher affinity for ET‐1 receptors, whereas addition of bosentan to a macitentan maximally efficacious background dose did not produce additional decreases in MAP …”

Section: Macitentan Early Development: Preclinical and Phase I And Iimentioning

confidence: 96%

“…Macitentan had an additive effect on lowering MAP in bosentan-treated animals, demonstrating macitentan's relatively higher affinity for ET-1 receptors, whereas addition of bosentan to a macitentan maximally efficacious background dose did not produce additional decreases in MAP. 82 In the Sugen-hypoxia experimental model of PAH, which induces PAH using the vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 in combination with hypobaric hypoxia, macitentan decreased right ventricular systolic pressure and attenuated right ventricular hypertrophy relative to vehicle-treated rats, and reduced the proportion of occlusive lesions. 83 Macitentan dose-dependently decreased mean pulmonary arterial pressure in monocrotalineinduced PAH in Wistar rats after single oral-dose administration (Actelion Ltd., data on file).…”

Section: Macitentan Early Development: Preclinical and Phase I And Iimentioning

confidence: 99%

Development of macitentan for the treatment of pulmonary arterial hypertension

Selej

Romero

Channick

et al. 2015

Annals of the New York Academy of Sciences

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Pulmonary arterial hypertension (PAH) is a serious, chronic condition that without early recognition and treatment leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles, compared with previous compounds. Macitentan's efficacy was demonstrated in an eventdriven morbidity and mortality study of treatment-naive and background PAH therapytreated symptomatic patients. Compared to placebo, 10 mg of macitentan significantly reduced the relative risk of morbidity and mortality by 45%, primarily by delaying PAH worsening, most prominently in World Health Organization (WHO) functional class (FC) II and III patients. Macitentan reduced the incidence of the composite end point of PAH-related hospitalizations and mortality and improved WHO FC and exercise capacity (6-min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long-term progression and reducing PAH-related hospitalizations, has changed treatment paradigms from goal-directed to long-term outcome-oriented therapy.

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Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension

Abstract: The add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.

Cited by 38 publications

References 15 publications

Novel Dual Endothelin Receptor Antagonist Macitentan Reverses Severe Pulmonary Arterial Hypertension in Rats

Novel Dual Endothelin Receptor Antagonist Macitentan Reverses Severe Pulmonary Arterial Hypertension in Rats

Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension: extended study results

Development of macitentan for the treatment of pulmonary arterial hypertension

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