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Marius M Hoeper - One of the best experts on this subject based on the ideXlab platform.

  • long term results from the early study of Bosentan in who functional class ii pulmonary arterial hypertension patients
    International Journal of Cardiology, 2014
    Co-Authors: Gerald Simonneau, Marius M Hoeper, Nazzareno Galie, Andjela Kusicpajic, Jean Christophe Lemarie, Pavel Jansa, Gisela Meyer, Hikmet Alhiti, Lewis J Rubin
    Abstract:

    Abstract Background The double-blind phase of the EARLY study of Bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with Bosentan in the open-label extension phase of the EARLY study. Methods Exploratory efficacy outcomes included 6-minute walk distance (6MWD) and WHO FC. Adverse events were recorded. Kaplan–Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival. Results Median exposure to Bosentan ( n =173) was 51months. At the end of the Bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of Bosentan in 20.2% of patients. Aminotransferase elevations >3× upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death. Conclusions The majority of patients exposed to long-term Bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.

  • Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension benefit Bosentan effects in inoperable forms of chronic thromboembolic pulmonary hypertension a randomized placebo controlled trial
    Journal of the American College of Cardiology, 2008
    Co-Authors: Xavier Jais, Marius M Hoeper, Hossein Ardeschir Ghofrani, Adam Torbicki, Marion Delcroix, Andrea Maria Darmini, Pavel Jansa, Irene M Lang, Eckhard Mayer, Joanna Pepkezaba
    Abstract:

    Objectives Our goal was to investigate the effect of treatment with the oral dual endothelin receptor antagonist Bosentan on the hemodynamics and exercise capacity of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Background CTEPH is characterized by vascular obstruction and remodeling, leading to increased pulmonary vascular resistance (PVR). Although pulmonary endarterectomy (PEA) is potentially curative, medical therapy is needed in patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA. Methods The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment with Bosentan or placebo. Secondary end points included change from baseline in World Health Organization functional class and other hemodynamic parameters. Results One hundred fifty-seven patients were enrolled and randomized: 80 to placebo, 77 to Bosentan. A statistically significant treatment effect (TE) of Bosentan over placebo on PVR was demonstrated: −24.1% of baseline (95% confidence interval [CI]: −31.5% to −16.0%; p −5 ; 95% CI: −283 to −104 dyn·s·cm −5 ; p −1 ·m −2 ; 95% CI: 0.14 to 0.46 l·min −1 ·m −2 ; p = 0.0007) improved. Mean TE on 6-min walk distance was +2.2 m (95% CI: −22.5 to 26.8 m; p = 0.5449). Bosentan treatment was well tolerated. Conclusions This study demonstrated a positive TE of Bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension; NCT00313222 ).

  • safety experience with Bosentan in 146 children 2 11 years old with pulmonary arterial hypertension results from the european postmarketing surveillance program
    Pediatric Research, 2008
    Co-Authors: Maurice Beghetti, Marius M Hoeper, Eleanor S Segal, David G Kiely, B Schwierin, Joern Carlsen, Marc Humbert
    Abstract:

    The oral dual endothelin receptor antagonist Bosentan has been shown to improve the short- and medium-term course of adult pulmonary arterial hypertension (PAH); however, data from clinical studies in children are limited. This analysis investigated the safety profile of Bosentan in pediatric patients in a European, pro- spective, noninterventional, Internet-based postmarketing surveil- lance database (Tracleer PMS). Pediatric patients (aged 2-11 y) were compared with patients aged 12 y. Over a 30-mo period, 4994 patients, including 146 Bosentan-naive pediatric patients (51.4% males), were captured in the database. Predominant etiologies in children were idiopathic PAH (40.4%) and PAH related to congenital heart disease (45.2%). The majority of children were in New York Heart Association functional class II (28.1%) or III (50.7%), and median exposure to Bosentan was 29.1 wk. Elevated aminotrans- ferases were reported in 2.7% of children versus 7.8% of patients 12 y. The discontinuation rate was 14.4% in children versus 28.1% in patients 12 y. The Tracleer PMS results provide unique infor- mation on pediatric PAH in Europe. They also suggest that Tracleer may be better tolerated in children than in adults. This observation confirms the value of monthly monitoring of liver function for the duration of Bosentan treatment. (Pediatr Res 64: 200-204, 2008)

  • safety experience with Bosentan in 146 children 2 11 years old with pulmonary arterial hypertension results from the european postmarketing surveillance program
    Pediatric Research, 2008
    Co-Authors: Maurice Beghetti, Marius M Hoeper, Eleanor S Segal, David G Kiely, B Schwierin, Joern Carlsen, Marc Humbert
    Abstract:

    The oral dual endothelin receptor antagonist Bosentan has been shown to improve the short- and medium-term course of adult pulmonary arterial hypertension (PAH); however, data from clinical studies in children are limited. This analysis investigated the safety profile of Bosentan in pediatric patients in a European, prospective, noninterventional, Internet-based postmarketing surveillance database (Tracleer PMS). Pediatric patients (aged 2-11 y) were compared with patients aged > or =12 y. Over a 30-mo period, 4994 patients, including 146 Bosentan-naive pediatric patients (51.4% males), were captured in the database. Predominant etiologies in children were idiopathic PAH (40.4%) and PAH related to congenital heart disease (45.2%). The majority of children were in New York Heart Association functional class II (28.1%) or III (50.7%), and median exposure to Bosentan was 29.1 wk. Elevated aminotransferases were reported in 2.7% of children versus 7.8% of patients > or =12 y. The discontinuation rate was 14.4% in children versus 28.1% in patients > or =12 y. The Tracleer PMS results provide unique information on pediatric PAH in Europe. They also suggest that Tracleer may be better tolerated in children than in adults. This observation confirms the value of monthly monitoring of liver function for the duration of Bosentan treatment.

  • experience with inhaled iloprost and Bosentan in portopulmonary hypertension
    European Respiratory Journal, 2007
    Co-Authors: Marius M Hoeper, Gert Hoeffken, Edda Spiekerkoetter, Tobias Welte, Hans-juergen Seyfarth, H Wirtz, Mathias W Pletz, Michael Halank
    Abstract:

    Novel treatments, such as prostanoids or endothelin receptor antagonists, have been introduced for various forms of pulmonary arterial hypertension, but the long-term effects of these treatments on portopulmonary hypertension (PPHT) are unknown. In a retrospective analysis, the present authors assessed the safety and efficacy of inhaled iloprost, a prostacyclin analogue, and Bosentan, an endothelin receptor antagonist, in patients with PPHT. In total, 31 consecutive patients with Child class A or B cirrhosis and severe PPHT were treated for up to 3 yrs with either inhaled iloprost (n = 13) or Bosentan (n = 18), and the effects on exercise capacity, haemodynamics and survival were evaluated. In the iloprost group, the survival rates at 1, 2 and 3 yrs were 77, 62 and 46%, respectively. In the Bosentan group, the respective survival rates were 94, 89 and 89%. Event-free survival rates, i.e. survival without transplantation, right heart failure or clinical worsening requiring the introduction of a new treatment for pulmonary hypertension, was also significantly better in the Bosentan group. Bosentan had significantly better effects than inhaled iloprost on exercise capacity, as determined by the 6-min walk test, as well as on haemodynamics. Both treatments proved to be safe, especially in regards of liver function. In the present series of patients with well-preserved liver function and severe portopulmonary hypertension, treatment with both inhaled iloprost and Bosentan appeared to be safe. Patients treated with Bosentan had higher survival rates, but prospective controlled studies are required to confirm these findings.

Marc Humbert - One of the best experts on this subject based on the ideXlab platform.

  • cyp2c9 slco1b1 slco1b3 and abcb11 polymorphisms in patients with Bosentan induced liver toxicity
    Clinical Pharmacology & Therapeutics, 2014
    Co-Authors: Matthieu Roustit, Xavier Fonrose, David Montani, Barbara Girerd, Marc Humbert, Jean-luc Cracowski, Francoise Stankelabesque, N Gonnet
    Abstract:

    Bosentan is an endothelin receptor antagonist used as a first-line treatment in pulmonary arterial hypertension (PAH). Its main adverse effect is a dose-dependent liver toxicity. CYP2C9*2 has recently been shown to be associated with hepatotoxicity in PAH patients. We conducted a nested case-control study to further explore the relationship between functional polymorphisms of gene products involved in Bosentan pharmacokinetics (OATP1B1, OATP1B3, and CYP2C9) or hepatobiliary transporters affected by Bosentan (ABCB11) and Bosentan-induced liver toxicity.

  • safety experience with Bosentan in 146 children 2 11 years old with pulmonary arterial hypertension results from the european postmarketing surveillance program
    Pediatric Research, 2008
    Co-Authors: Maurice Beghetti, Marius M Hoeper, Eleanor S Segal, David G Kiely, B Schwierin, Joern Carlsen, Marc Humbert
    Abstract:

    The oral dual endothelin receptor antagonist Bosentan has been shown to improve the short- and medium-term course of adult pulmonary arterial hypertension (PAH); however, data from clinical studies in children are limited. This analysis investigated the safety profile of Bosentan in pediatric patients in a European, pro- spective, noninterventional, Internet-based postmarketing surveil- lance database (Tracleer PMS). Pediatric patients (aged 2-11 y) were compared with patients aged 12 y. Over a 30-mo period, 4994 patients, including 146 Bosentan-naive pediatric patients (51.4% males), were captured in the database. Predominant etiologies in children were idiopathic PAH (40.4%) and PAH related to congenital heart disease (45.2%). The majority of children were in New York Heart Association functional class II (28.1%) or III (50.7%), and median exposure to Bosentan was 29.1 wk. Elevated aminotrans- ferases were reported in 2.7% of children versus 7.8% of patients 12 y. The discontinuation rate was 14.4% in children versus 28.1% in patients 12 y. The Tracleer PMS results provide unique infor- mation on pediatric PAH in Europe. They also suggest that Tracleer may be better tolerated in children than in adults. This observation confirms the value of monthly monitoring of liver function for the duration of Bosentan treatment. (Pediatr Res 64: 200-204, 2008)

  • safety experience with Bosentan in 146 children 2 11 years old with pulmonary arterial hypertension results from the european postmarketing surveillance program
    Pediatric Research, 2008
    Co-Authors: Maurice Beghetti, Marius M Hoeper, Eleanor S Segal, David G Kiely, B Schwierin, Joern Carlsen, Marc Humbert
    Abstract:

    The oral dual endothelin receptor antagonist Bosentan has been shown to improve the short- and medium-term course of adult pulmonary arterial hypertension (PAH); however, data from clinical studies in children are limited. This analysis investigated the safety profile of Bosentan in pediatric patients in a European, prospective, noninterventional, Internet-based postmarketing surveillance database (Tracleer PMS). Pediatric patients (aged 2-11 y) were compared with patients aged > or =12 y. Over a 30-mo period, 4994 patients, including 146 Bosentan-naive pediatric patients (51.4% males), were captured in the database. Predominant etiologies in children were idiopathic PAH (40.4%) and PAH related to congenital heart disease (45.2%). The majority of children were in New York Heart Association functional class II (28.1%) or III (50.7%), and median exposure to Bosentan was 29.1 wk. Elevated aminotransferases were reported in 2.7% of children versus 7.8% of patients > or =12 y. The discontinuation rate was 14.4% in children versus 28.1% in patients > or =12 y. The Tracleer PMS results provide unique information on pediatric PAH in Europe. They also suggest that Tracleer may be better tolerated in children than in adults. This observation confirms the value of monthly monitoring of liver function for the duration of Bosentan treatment.

  • results of european post marketing surveillance of Bosentan in pulmonary hypertension
    European Respiratory Journal, 2007
    Co-Authors: Marc Humbert, Eleanor S Segal, David G Kiely, Jorn Carlsen, B Schwierin, Marius M Hoeper
    Abstract:

    After the approval of Bosentan for the treatment of pulmonary arterial hypertension (PAH), European authorities required the introduction of a post-marketing surveillance system (PMS) to obtain further data on its safety profile. A novel, prospective, internet-based PMS was designed, which solicited reports on elevated aminotransferases, medical reasons for Bosentan discontinuation and other serious adverse events requiring hospitalisation. Data captured included demographics, PAH aetiology, baseline functional status and concomitant PAH-specific medications. Safety signals captured included death, hospitalisation, serious adverse events, unexpected adverse events and elevated aminotransferases. Within 30 months, 4,994 patients were included, representing 79% of patients receiving Bosentan in Europe. In total, 4,623 patients were naive to treatment; of these, 352 had elevated aminotransferases, corresponding to a crude incidence of 7.6% and an annual rate of 10.1%. Bosentan was discontinued due to elevated aminotransferases in 150 (3.2%) Bosentan-naive patients. Safety results were consistent across subgroups and aetiologies. The novel post-marketing surveillance captured targeted safety data ("potential safety signals") from the majority of patients and confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials. These data complement those from randomised controlled clinical trials and provide important additional information on the safety profile of Bosentan.

  • Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease a subgroup analysis of the pivotal clinical trials and their open label extensions
    Annals of the Rheumatic Diseases, 2006
    Co-Authors: Christopher P Denton, Marc Humbert, Lewis J Rubin, C M Black
    Abstract:

    Background: Endothelin-1 is considered to be a central pathogenic factor in connective tissue diseases (CTDs) such as systemic sclerosis (SSc), leading to vasoconstriction, fibrosis, hypertrophy and inflammation. A frequent complication of CTD is pulmonary arterial hypertension (PAH), which has a major effect on functioning and quality of life, and is associated with a particularly poor prognosis. Objective: To present a subgroup analysis that summarises experiences from the pivotal studies and their open-label extensions with the oral dual endothelin-1 receptor antagonist Bosentan in patients with PAH and CTD, mostly SSc and lupus erythematosus. Methods: 66 patients with PAH secondary to CTD, in World Health Organization functional class III or IV, were randomised to two double-blind, placebo-controlled studies and followed up for 12 and 16 weeks, respectively. The primary end point was change in exercise capacity, assessed using the 6-min walk test. In both studies and their extensions, survival was assessed from start of treatment to death or data cut-off and analysed as Kaplan–Meier estimates. Results: 44 patients with PAH secondary to CTD who were treated with Bosentan were stable in 6-min walk distance at the end of the study (+19.5 m, 95% confidence interval (CI) −3.2 to 42.2), whereas patients treated with placebo deteriorated (−2.6 m, 95% CI −54.0 to 48.7). 64 patients subsequently received Bosentan in an open-label long-term extension study. Mean (standard deviation (SD)) exposure to Bosentan was 1.6 (0.9) years, and duration of observation was 1.8 (0.8) years. 8 (16%) patients received epoprostenol as add-on treatment and 7 (14%) after discontinuation of Bosentan. Survival in those receiving Bosentan was 85.9% after 1 year and 73.4% after 2 years. Conclusion: Short-term Bosentan treatment in a subgroup of patients with PAH secondary to CTD seems to have a favourable effect compared with placebo. The long-term follow-up of these patients suggests that first-line Bosentan, with the subsequent addition of other PAH treatments if required, is safe for long-term treatment and may have a positive effect on outcome.

Maurice Beghetti - One of the best experts on this subject based on the ideXlab platform.

  • Bosentan as adjunctive therapy for persistent pulmonary hypertension of the newborn results of the randomized multicenter placebo controlled exploratory trial
    The Journal of Pediatrics, 2016
    Co-Authors: Robin H Steinhorn, Jeffrey R Fineman, Andjela Kusicpajic, Peter Cornelisse, Martine Gehin, Pegah Nowbakht, Christine Pierce, Maurice Beghetti
    Abstract:

    Objective To evaluate the efficacy, safety, and pharmacokinetics of the endothelin receptor antagonist Bosentan as adjunctive therapy for neonates with persistent pulmonary hypertension of the newborn (PPHN). Study design This was a phase 3, multicenter, randomized, placebo-controlled exploratory trial (FUTURE-4). Eligible patients were >34 weeks gestation, Results Twenty-one neonates received a study drug (13 Bosentan, 8 placebo). Compared with the placebo group, the group treated with Bosentan had a higher median baseline OI and greater need for vasoactive agents. One treatment failure (need for extracorporeal membrane oxygenation) occurred in the group treated with Bosentan. The time to weaning from iNO or mechanical ventilation was not different between the groups. Bosentan was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminase levels. Anemia and edema were more frequent in patients receiving Bosentan. Blood concentrations of Bosentan were low and variable on day 1, and achieved steady state on day 5. Conclusion Adjunctive Bosentan was well tolerated, but did not improve oxygenation or other outcomes in our patients with PPHN. This effect may be related to delayed absorption of Bosentan on treatment initiation in critically ill neonates or to more severe illness of the neonates who received Bosentan. Trial registration ClinicalTrials.gov: NCT01389856

  • abstract 13503 Bosentan as adjunctive therapy for persistent pulmonary hypertension of the newborn results of the future 4 study
    Circulation, 2014
    Co-Authors: Robin H Steinhorn, Jeffrey R Fineman, Andjela Kusicpajic, Peter Cornelisse, Martine Gehin, Pegah Nowbakht, Christine Pierce, Maurice Beghetti
    Abstract:

    Background: Inhaled nitric oxide (iNO) is the mainstay of therapy for persistent pulmonary hypertension of the newborn (PPHN), but does not fully reverse PPHN in at least 30% of cases. Endothelin levels are elevated in PPHN, leading to consideration of endothelin receptor antagonists as adjunctive therapy. Methods: This was a Phase 3, multi-center, randomized, placebo controlled trial to evaluate the efficacy and safety of Bosentan in neonates with PPHN. Eligible patients were ≤34 weeks gestation, < 7days of age, and with persistent respiratory failure (defined as oxygenation index (OI) ≤12) after at least 4 hours of iNO treatment. After 2:1 randomization, Bosentan 2 mg/kg or matching placebo was given by nasogastric tube twice daily for at least 48 hours, and up to 1 day after iNO weaning. Results: During the 2-year study period, 21 eligible neonates from 9 centers received study drug (13 Bosentan, 8 placebo). The groups had similar gestational age, weight, and sex distribution. The Bosentan group had higher baseline OI values and rates of parenchymal lung disease than placebo (Table). On Day 1, Bosentan concentrations were low and highly variable. Steady-state conditions comparable to those observed in adult PAH patients were achieved by Day 5. Bosentan was well tolerated, and did not adversely affect systemic blood pressure or hepatic transaminases. Adverse events of anemia and edema were more frequent in the Bosentan group, but none led to treatment discontinuation. Treatment failure (need for ECMO) and time to weaning from iNO or mechanical ventilation were not different between groups. Cox Proportional Hazards analysis showed that higher baseline OI increased time to weaning from iNO (p=0.007). Conclusions: Adjunctive Bosentan was well tolerated, but did not improve oxygenation or other outcomes in PPHN. This may be related to delayed absorption of Bosentan in young, critically ill neonates. Additionally, baseline OI strongly affects weaning time from iNO. ![][1] [1]: /embed/graphic-1.gif

  • pharmacokinetic and clinical profile of a novel formulation of Bosentan in children with pulmonary arterial hypertension the future 1 study
    British Journal of Clinical Pharmacology, 2009
    Co-Authors: Maurice Beghetti, Robyn J Barst, Sheila G Haworth, Damien Bonnet, P Acar, Alain Fraisse, Dunbar D Ivy, Xavier Jais, Ingram Schulzeneick, Nazzareno Galie
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Exposure to Bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg−1 when compared with adult PAH patients. • In healthy adult subjects, Bosentan pharmacokinetics are less than dose-proportional at doses of ≥500 mg. WHAT THIS STUDY ADDS • The pharmacokinetics of a new paediatric Bosentan formulation were characterized in paediatric PAH patients. • The level of exposure to Bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. • In paediatric PAH patients, nondose-proportional pharmacokinetics of Bosentan occur at lower doses when compared with healthy adult subjects. AIM To show equivalent Bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with Bosentan 2 mg kg−1 b.i.d. and then for 8 weeks with 4 mg kg−1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration–time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to Bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg−1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in Bosentan-naive patients, whereas the rare worsenings occurred in patients already on Bosentan prior to study initiation. The paediatric formulation was well accepted and Bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS Exposure to Bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit–risk profile for Bosentan at 2 mg kg−1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerated.

  • safety experience with Bosentan in 146 children 2 11 years old with pulmonary arterial hypertension results from the european postmarketing surveillance program
    Pediatric Research, 2008
    Co-Authors: Maurice Beghetti, Marius M Hoeper, Eleanor S Segal, David G Kiely, B Schwierin, Joern Carlsen, Marc Humbert
    Abstract:

    The oral dual endothelin receptor antagonist Bosentan has been shown to improve the short- and medium-term course of adult pulmonary arterial hypertension (PAH); however, data from clinical studies in children are limited. This analysis investigated the safety profile of Bosentan in pediatric patients in a European, pro- spective, noninterventional, Internet-based postmarketing surveil- lance database (Tracleer PMS). Pediatric patients (aged 2-11 y) were compared with patients aged 12 y. Over a 30-mo period, 4994 patients, including 146 Bosentan-naive pediatric patients (51.4% males), were captured in the database. Predominant etiologies in children were idiopathic PAH (40.4%) and PAH related to congenital heart disease (45.2%). The majority of children were in New York Heart Association functional class II (28.1%) or III (50.7%), and median exposure to Bosentan was 29.1 wk. Elevated aminotrans- ferases were reported in 2.7% of children versus 7.8% of patients 12 y. The discontinuation rate was 14.4% in children versus 28.1% in patients 12 y. The Tracleer PMS results provide unique infor- mation on pediatric PAH in Europe. They also suggest that Tracleer may be better tolerated in children than in adults. This observation confirms the value of monthly monitoring of liver function for the duration of Bosentan treatment. (Pediatr Res 64: 200-204, 2008)

  • safety experience with Bosentan in 146 children 2 11 years old with pulmonary arterial hypertension results from the european postmarketing surveillance program
    Pediatric Research, 2008
    Co-Authors: Maurice Beghetti, Marius M Hoeper, Eleanor S Segal, David G Kiely, B Schwierin, Joern Carlsen, Marc Humbert
    Abstract:

    The oral dual endothelin receptor antagonist Bosentan has been shown to improve the short- and medium-term course of adult pulmonary arterial hypertension (PAH); however, data from clinical studies in children are limited. This analysis investigated the safety profile of Bosentan in pediatric patients in a European, prospective, noninterventional, Internet-based postmarketing surveillance database (Tracleer PMS). Pediatric patients (aged 2-11 y) were compared with patients aged > or =12 y. Over a 30-mo period, 4994 patients, including 146 Bosentan-naive pediatric patients (51.4% males), were captured in the database. Predominant etiologies in children were idiopathic PAH (40.4%) and PAH related to congenital heart disease (45.2%). The majority of children were in New York Heart Association functional class II (28.1%) or III (50.7%), and median exposure to Bosentan was 29.1 wk. Elevated aminotransferases were reported in 2.7% of children versus 7.8% of patients > or =12 y. The discontinuation rate was 14.4% in children versus 28.1% in patients > or =12 y. The Tracleer PMS results provide unique information on pediatric PAH in Europe. They also suggest that Tracleer may be better tolerated in children than in adults. This observation confirms the value of monthly monitoring of liver function for the duration of Bosentan treatment.

Robyn J Barst - One of the best experts on this subject based on the ideXlab platform.

  • tadalafil monotherapy and as add on to background Bosentan in patients with pulmonary arterial hypertension
    Journal of Heart and Lung Transplantation, 2011
    Co-Authors: Robyn J Barst, Anthony Beardsworth, David P Sundin, Bruce H. Brundage, Hossein Ardeschir Ghofrani, Ronald J Oudiz, Nazzareno Galie
    Abstract:

    Background Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background Bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to Bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups. Methods Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background Bosentan + PBO; and background Bosentan + tadalafil. Patients randomized to tadalafil or PBO ( N = 405) were analyzed by Bosentan use (yes = 216, no=189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW. Results At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: −2 to 48 m; n = 42) for tadalafil 40 mg add-on to Bosentan. The 6MWD for treatment-naive and background Bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background Bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar. Conclusion Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background Bosentan, but data are insufficient to conclude additional benefit.

  • long term outcomes in children with pulmonary arterial hypertension treated with Bosentan in real world clinical settings
    American Journal of Cardiology, 2010
    Co-Authors: Dunbar D Ivy, Jean Christophe Lemarie, Erika B Rosenzweig, Monika Brand, Daniel W Rosenberg, Robyn J Barst
    Abstract:

    Treatment algorithms in pediatric pulmonary arterial hypertension (PAH) are derived from clinical trials in adult populations and from clinical practice, but experience in children is limited. In this retrospective cohort study, we analyzed outcomes in a previously identified cohort of 86 consecutive children with PAH treated with Bosentan as part of their treatment regimen. All children with idiopathic PAH or heritable PAH and PAH associated with congenital heart disease or connective tissue disease who started Bosentan treatment from May 2001 to April 2003 in 2 tertiary pediatric referral centers were followed, with data collection ending August 2006. Eighty-six children (37 male, 49 female) 11 ± 5 years of age with idiopathic/heritable PAH (n = 36), PAH associated with congenital heart disease (n = 48), or PAH associated with connective tissue disease (n = 2) received Bosentan as monotherapy (n = 42) or as an add-on to pre-existing continuous intravenous epoprostenol or subcutaneous treprostinil (n = 44). Median observation period was 39 months (range 2 to 60). Thirty-four patients (40%) received ≥1 additional PAH-specific therapy during follow-up. At end of data collection, 25 patients (29%) remained on Bosentan, 43 (50%) had stopped Bosentan, 11 (13%) had died while on Bosentan, and 7 were lost to follow-up. At 4 years, the Kaplan-Meier estimate of disease progression in patients while on Bosentan was 54% (7 patients at risk) with a survival estimate of 82% (16 patients at risk). Risk factors significantly associated with survival were World Health Organization functional class and indexed pulmonary vascular resistance. In conclusion, outcome in children with PAH managed with current treatment regimens appears favorable. However, despite current therapy options, disease progression remains a concern.

  • pharmacokinetic and clinical profile of a novel formulation of Bosentan in children with pulmonary arterial hypertension the future 1 study
    British Journal of Clinical Pharmacology, 2009
    Co-Authors: Maurice Beghetti, Robyn J Barst, Sheila G Haworth, Damien Bonnet, P Acar, Alain Fraisse, Dunbar D Ivy, Xavier Jais, Ingram Schulzeneick, Nazzareno Galie
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Exposure to Bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg−1 when compared with adult PAH patients. • In healthy adult subjects, Bosentan pharmacokinetics are less than dose-proportional at doses of ≥500 mg. WHAT THIS STUDY ADDS • The pharmacokinetics of a new paediatric Bosentan formulation were characterized in paediatric PAH patients. • The level of exposure to Bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. • In paediatric PAH patients, nondose-proportional pharmacokinetics of Bosentan occur at lower doses when compared with healthy adult subjects. AIM To show equivalent Bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with Bosentan 2 mg kg−1 b.i.d. and then for 8 weeks with 4 mg kg−1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration–time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to Bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg−1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in Bosentan-naive patients, whereas the rare worsenings occurred in patients already on Bosentan prior to study initiation. The paediatric formulation was well accepted and Bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS Exposure to Bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit–risk profile for Bosentan at 2 mg kg−1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerated.

  • sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing Bosentan
    Journal of Heart and Lung Transplantation, 2007
    Co-Authors: Raymond L Benza, A Keogh, Ronald J Oudiz, Sanjay Mehta, Clinton E Lawrence, Robyn J Barst
    Abstract:

    Background Bosentan, an oral ET A /ET B receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH). However, some patients discontinue Bosentan because of hepatotoxicity or inadequate efficacy. Sitaxsentan, an oral, ET A -selective endothelin antagonist currently under investigation, may be an alternative treatment option. In this study we evaluate the safety and efficacy of sitaxsentan in patients discontinuing Bosentan. Methods Forty-eight patients with idiopathic PAH or PAH associated with connective-tissue disease or congenital heart disease were randomized (double-blind) to a single daily dose of either 50 mg or 100 mg sitaxsentan. Thirty-five of the 48 patients discontinued Bosentan because of inadequate efficacy, as judged by the investigator, and 13 discontinued Bosentan for safety concerns. Study end-points included change in 6-minute walk distance (6MWD), change in World Health Organization (WHO) functional class, time to clinical worsening, and change in Borg dyspnea score (Borg) from baseline to Week 12. Results With 100 mg sitaxsentan, 5 of 15 patients (33%) who discontinued Bosentan because inadequate efficacy improved, demonstrating a >15% increase in 6MWD, vs 2 of 20 patients (10%) treated with 50 mg sitaxsentan. Fifteen percent and 20% of these patients had a >15% decrease in 6MWD in the 50- and 100-mg groups, respectively. Similar results were seen for the Borg and WHO functional class. Of the 12 patients discontinuing Bosentan because of hepatotoxicity, 1 developed elevated liver enzymes at 13 weeks of sitaxsentan therapy. Overall, sitaxsentan was well tolerated. Conclusions Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing Bosentan.

  • survival in patients with class iii idiopathic pulmonary arterial hypertension treated with first line oral Bosentan compared with an historical cohort of patients started on intravenous epoprostenol
    Thorax, 2005
    Co-Authors: Olivier Sitbon, Robyn J Barst, Nazzareno Galie, Marc Humbert, Maurizio Rainisio, David B Badesch, Lewis J Rubin, Vallerie V Mclaughlin, C M Black, Gerald Simonneau
    Abstract:

    Background: The oral dual endothelin receptor antagonist Bosentan improves exercise capacity and delays clinical worsening in patients with pulmonary arterial hypertension, but its use could delay starting intravenous epoprostenol, a life saving treatment. Methods: Survival in patients with functional class III idiopathic pulmonary arterial hypertension (PAH) treated with Bosentan in clinical trials was compared with historical data from similar patients treated with epoprostenol in the clinic. Statistical methods were used to adjust for possible underlying differences between the two groups. Results: Baseline factors for the 139 patients treated with Bosentan and the 346 treated with epoprostenol suggested that the epoprostenol cohort had more severe disease—that is, a lower cardiac index (2.01 v 2.39 l/min/m2) and higher pressures and resistance. Kaplan-Meier survival estimates after 1 and 2 years were 97% and 91%, respectively, in the Bosentan cohort and 91% and 84% in the epoprostenol cohort. Cox regression analyses adjusting for differences in baseline factors showed a greater probability of death in the epoprostenol cohort (hazard ratio 2.2 (95% confidence interval 1.2 to 4.0) in the model adjusted for haemodynamics). Alternative regression analyses and analyses to adjust for different data collection dates gave consistently similar results. When matched cohorts of 83 patients each were selected, survival estimates were similar. In the Bosentan cohort 87% and 75% of patients followed for 1 and 2 years, respectively, remained on monotherapy. Conclusions: No evidence was found to suggest that initial treatment with oral Bosentan, followed by or with the addition of other treatment if needed, adversely affected the long term outcome compared with initial intravenous epoprostenol in patients with class III idiopathic PAH.

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  • long term results from the early study of Bosentan in who functional class ii pulmonary arterial hypertension patients
    International Journal of Cardiology, 2014
    Co-Authors: Gerald Simonneau, Marius M Hoeper, Nazzareno Galie, Andjela Kusicpajic, Jean Christophe Lemarie, Pavel Jansa, Gisela Meyer, Hikmet Alhiti, Lewis J Rubin
    Abstract:

    Abstract Background The double-blind phase of the EARLY study of Bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with Bosentan in the open-label extension phase of the EARLY study. Methods Exploratory efficacy outcomes included 6-minute walk distance (6MWD) and WHO FC. Adverse events were recorded. Kaplan–Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival. Results Median exposure to Bosentan ( n =173) was 51months. At the end of the Bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of Bosentan in 20.2% of patients. Aminotransferase elevations >3× upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death. Conclusions The majority of patients exposed to long-term Bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.

  • tadalafil monotherapy and as add on to background Bosentan in patients with pulmonary arterial hypertension
    Journal of Heart and Lung Transplantation, 2011
    Co-Authors: Robyn J Barst, Anthony Beardsworth, David P Sundin, Bruce H. Brundage, Hossein Ardeschir Ghofrani, Ronald J Oudiz, Nazzareno Galie
    Abstract:

    Background Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background Bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to Bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups. Methods Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background Bosentan + PBO; and background Bosentan + tadalafil. Patients randomized to tadalafil or PBO ( N = 405) were analyzed by Bosentan use (yes = 216, no=189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW. Results At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: −2 to 48 m; n = 42) for tadalafil 40 mg add-on to Bosentan. The 6MWD for treatment-naive and background Bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background Bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar. Conclusion Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background Bosentan, but data are insufficient to conclude additional benefit.

  • pharmacokinetic and clinical profile of a novel formulation of Bosentan in children with pulmonary arterial hypertension the future 1 study
    British Journal of Clinical Pharmacology, 2009
    Co-Authors: Maurice Beghetti, Robyn J Barst, Sheila G Haworth, Damien Bonnet, P Acar, Alain Fraisse, Dunbar D Ivy, Xavier Jais, Ingram Schulzeneick, Nazzareno Galie
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Exposure to Bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg−1 when compared with adult PAH patients. • In healthy adult subjects, Bosentan pharmacokinetics are less than dose-proportional at doses of ≥500 mg. WHAT THIS STUDY ADDS • The pharmacokinetics of a new paediatric Bosentan formulation were characterized in paediatric PAH patients. • The level of exposure to Bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. • In paediatric PAH patients, nondose-proportional pharmacokinetics of Bosentan occur at lower doses when compared with healthy adult subjects. AIM To show equivalent Bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with Bosentan 2 mg kg−1 b.i.d. and then for 8 weeks with 4 mg kg−1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration–time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to Bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg−1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in Bosentan-naive patients, whereas the rare worsenings occurred in patients already on Bosentan prior to study initiation. The paediatric formulation was well accepted and Bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS Exposure to Bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit–risk profile for Bosentan at 2 mg kg−1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerated.

  • longer term Bosentan therapy improves functional capacity in eisenmenger syndrome results of the breathe 5 open label extension study
    International Journal of Cardiology, 2008
    Co-Authors: Michael A Gatzoulis, Nazzareno Galie, Maurice Beghetti, John T Granton, Rolf M F Berger, Andrea Lauer, Eleonora Chiossi, Michael J Landzberg
    Abstract:

    BACKGROUND: Bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, improves hemodynamics and exercise capacity in patients with Eisenmenger syndrome but longer-term effects are unknown. This study investigated the efficacy and safety of Bosentan up to 40 weeks in these patients. METHODS: Following the 16-week, double blind, placebo-controlled BREATHE-5 study of Bosentan in patients with Eisenmenger syndrome, an open-label extension (OLE) was performed. Patients who completed BREATHE-5 received Bosentan for an additional 24 weeks (62.5 mg b.i.d. for 4 weeks, then 125 mg b.i.d.) and were analyzed in two groups; ex-placebo and ex-Bosentan, according to BREATHE-5 treatment. RESULTS: Thirty-seven patients with Eisenmenger syndrome who participated in BREATHE-5 were included in the OLE. At week 24, the 6-minute walk distance (mean+/-SE) increased from OLE baseline for the ex-placebo (+33.2+/-23.9 m) and ex-Bosentan group (+6.7+/-10.0 m). The overall improvement from baseline of BREATHE-5 was +61.3+/-8.1 m (95% confidence interval: [44.7, 78.0]) for the ex-Bosentan group. WHO functional class was improved in both groups. Bosentan did not reduce systemic arterial blood oxygen saturation; safety profile was comparable to previous trials. CONCLUSIONS: In conclusion, these longer follow-up data support the efficacy and safety profile reported in the preceding BREATHE-5 study of Bosentan treatment of Eisenmenger syndrome, challenging the notion that pulmonary vascular disease and severe functional impairment in these patients are not amenable to therapy.

  • Bosentan therapy in patients with eisenmenger syndrome a multicenter double blind randomized placebo controlled study
    Circulation, 2006
    Co-Authors: Nazzareno Galie, Maurice Beghetti, Michael A Gatzoulis, Rolf M F Berger, Andrea Lauer, Eleonora Chiossi, John Granton, Michael J Landzberg
    Abstract:

    Background—Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease. Because Eisenmenger syndrome is associated with increased endothelin expression, patients may benefit from endothelin receptor antagonism. Theoretically, interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia. Methods and Results—The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) was a 16-week, multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of Bosentan, a dual endothelin receptor antagonist, on systemic pulse oximetry (primary safety end point) and pulmonary vascular resistance (primary efficacy end point) in patients with World Health Organization functional class III Eisenmenger syndrome. Hemodynamics were assessed by right- and left-heart catheterization. Secondary end points included exercise capacity assessed by 6-minute walk distance, additional hemodynamic parameters, functional capacity, and safety. Fifty-four patients were randomized 2:1 to Bosentan (n37) or placebo (n17) for 16 weeks. The placebo-corrected effect on systemic pulse oximetry was 1.0% (95% confidence interval, 0.7 to 2.8), demonstrating that Bosentan did not worsen oxygen saturation. Compared with placebo, Bosentan reduced pulmonary vascular resistance index (472.0 dyn e·s·c m 5 ; P0.0383). The mean pulmonary arterial pressure decreased (5.5 mm Hg; P0.0363), and the exercise capacity increased (53.1 m; P0.0079). Four patients discontinued as a result of adverse events, 2 (5%) in the Bosentan group and 2 (12%) in the placebo group. Conclusions—In this first placebo-controlled trial in patients with Eisenmenger syndrome, Bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation. (Circulation. 2006;114:48-54.)