Bosentan

Bosentan is a competitive and dual antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors.

A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.[Pubmed:28213957]

Br J Clin Pharmacol. 2017 Aug;83(8):1734-1744.

AIM: The aim of the present study was to investigate whether increasing the Bosentan dosing frequency from 2 mg kg(-1) twice daily (b.i.d.) to 2 mg kg(-1) three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from >/=3 months to <12 years of age) would increase exposure. METHODS: An open-label, prospective, randomized, multicentre, multiple-dose, phase III study was conducted. Patients (n = 64) were randomized 1:1 to receive oral doses of Bosentan of 2 mg kg(-1) b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to Bosentan over 24 h corrected to the 2 mg kg(-1) dose (AUC0-24C ). The maximum plasma concentration corrected to the 2 mg kg(-1) dose (CmaxC ), the time to reach the maximum plasma concentration (tmax ) and safety endpoints were also assessed. RESULTS: The geometric mean [95% confidence interval (CI)] for AUC0-24C was 8535 h.ng ml(-1) (6936, 10 504) and 7275 h.ng ml(-1) (5468, 9679) for 2 mg kg(-1) b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for CmaxC was 743 ng ml(-1) (573, 963) and 528 ng ml(-1) (386, 722) for 2 mg kg(-1) b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for tmax was 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg kg(-1) b.i.d. and t.i.d., respectively. The proportions of patients who experienced >/=1 adverse event were similar in the b.i.d. (66.7%) and t.i.d. (67.7%) groups. CONCLUSIONS: There appeared to be no clinically relevant difference in exposure to Bosentan, or in safety, when increasing the frequency of Bosentan dosing from b.i.d. to t.i.d. Therefore, the present study provides no indication that the dosing recommendation should be changed, and 2 mg kg(-1) b.i.d. remains the recommended dosing regimen for Bosentan in paediatric PAH patients.

Effect of bosentan is correlated with MMP-9/TIMP-1 ratio in bleomycin-induced pulmonary fibrosis.[Pubmed:28357073]

Biomed Rep. 2017 Feb;6(2):201-205.

Pulmonary fibrosis (PF) is a life-threatening non-tumorous disease characterized by progressive fibrosis and worsening lung function. Various drugs, such as bleomycin, can contribute to lung injury and PF, with lung injury potentially occurring in 10% of bleomycin users. Bleomycin is the most commonly used drug in the establishment of an animal model of PF in rats. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) serve an important role in controlling tissue organization and fibrosis following injury. The present study examined the effect of Bosentan on fibrotic lung tissue in rats administrated with bleomycin. In total, 48 Wistar rats were administrated with bleomycin, with or without Bosentan, while the control rats received saline. The lung tissues were microscopically examined by staining with hematoxylin and eosin and Masson's trichome. ELISA was also used to detect the MMP-9 and TIMP-1 concentrations in the plasma. The results indicated that the Bosentan-treated groups on the next day and the 15th day showed significant reversal of pathological findings. In addition, the concentrations of MMP-9 and TIMP-1 appeared to be altered following Bosentan treatment, improving the bleomycin-induced PF. Masson's trichome staining showed high collagen deposition in the lung tissue sections, which may be a direct result of the activity of MMP-9 and TIMP-1. Furthermore, the deposition of collagen was significantly inhibited in Bosentan-treated groups. In conclusion, these results demonstrated that Bosentan inhibited lung fibrosis induced by bleomycin and it may be used as an inhibitor of PF.

Functional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitro.[Pubmed:28300593]

Eur J Pharmacol. 2017 Jun 5;804:111-116.

BACKGROUND: Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ETA-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro. METHODS: Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of Bosentan (1-10microM), macitentan (0.03-0.3microM) or ambrisentan (0.1-1microM). RESULTS: All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pKB values: Bosentan, pulmonary artery 6.28+/-0.13 and radial artery 6.04+/-0.10; macitentan, pulmonary artery 8.02+/-0.13 and radial artery 7.49+/-0.08; and ambrisentan, pulmonary artery 7.38+/-0.13 and radial artery 6.96+/-0.10. CONCLUSIONS: Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pKB findings here show that there would be significant antagonism of endothelin-1 contraction in the pulmonary and radial arteries at therapeutic plasma levels. This functional assay confirms in human tissue that much higher plasma concentrations of endothelin-1 receptor antagonists are required to be effective than those predicted from binding or other biochemical assays.

Tolerability of Switch to Macitentan from Bosentan in Pulmonary Arterial Hypertension.[Pubmed:28257550]

South Med J. 2017 Mar;110(3):223-228.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a progressive disease that can be treated with several medications. Macitentan, an endothelin receptor antagonist (ERA), has received approval as a PAH therapy. We report our data regarding the tolerability in patients with PAH who were switched from Bosentan to macitentan. METHODS: At the Baylor Pulmonary Hypertension Program, 24 patients with PAH who had been taking Bosentan and were switched to macitentan were identified in this retrospective study. Data from these patients who switched from Bosentan 125 mg orally twice per day to macitentan 10 mg orally daily (between October 2013 and February 2015) when macitentan became commercially available were collected. Patients were advised to take their last evening dose of Bosentan and then take the first dose of macitentan the following morning within 12 to 24 hours of the last Bosentan dose. Baseline data and postswitch data, including 6-minute walk distance, brain naturietic peptide, alanine transaminase (ALT) and aspartate transaminase (AST) levels, World Health Organization Functional Class (WHO FC), Borg dyspnea score, presence of peripheral edema. RESULTS: At the time of the switch, the mean age was 58 +/- 13 (mean +/- standard deviation) years, the duration of disease was 6.6 +/- 4.4 years, 21 patients were women, 54% were white, and 25% had idiopathic PAH. The mean duration of follow-up after the switch was 5.7 +/- 1.5 months. The 6-minute walk distance was 344 +/- 106 m preswitch and 319 +/- 85 m postswitch (P = 0.18). Brain naturietic peptide levels were 91 +/- 170 pg/mL preswitch and 90 +/- 137 pg/mL postswitch (P = 0.93). At the time of the switch, 42% were WHO FC II and 50% had edema, and 55% had edema. AST and ALT remained unchanged postswitch. Two patients did not tolerate the switch to macitentan and had to be returned to Bosentan: one patient with portopulmonary hypertension developed elevated AST and ALT and the second patient's macitentan was stopped because of malaise and tachyarrhythmia. One patient who underwent a successful liver transplant had macitentan stopped following the transplant. CONCLUSIONS: A rapid switch from Bosentan to macitentan was well tolerated and safe with maintained WHO FC, with no significant change in edema and liver enzyme levels. The switch from Bosentan to macitentan eliminates the need for monthly liver function test monitoring and removes the potential for Bosentan treatment interruption.

Bosentan is a competitive and dual antagonist of endothelin-1 (ET) for the ETA and ETB receptors with Ki of 4.7 nM and 95 nM in human SMC, respectively.

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