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Canadian Respiratory Journal 2018Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations...
OBJECTIVES
Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication.
METHODS
Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments.
RESULTS
A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain.
CONCLUSIONS
Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.
Topics: Antihypertensive Agents; Bosentan; Cost-Benefit Analysis; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sildenafil Citrate; Vasodilator Agents
PubMed: 30581511
DOI: 10.1155/2018/1015239 -
Respiratory Care Aug 2013Pulmonary hypertension (PH) is a common consequence of COPD. It has been speculated that patients showing serious PH and vascular remodeling without severe airway...
Pulmonary hypertension (PH) is a common consequence of COPD. It has been speculated that patients showing serious PH and vascular remodeling without severe airway obstruction might benefit from vasoactive treatment. There is no approved drug available for COPD-induced PH. Most trials assessing the efficacy of vasoactive drugs in PH have had a follow-up of 12-16 weeks. We report on 4 subjects with COPD and PH. Pulmonary arterial hypertension associated diseases and pulmonary embolism were ruled out. PH persisted despite optimized treatment of underlying COPD and comorbidities, so bosentan was started in all 4 subjects. With bosentan the mean pulmonary artery pressure improved. The average gains in 6-min walk distance at 2-3 months and 8-9 months were 36 m and 145 m, respectively. The maximum gains in 6-min walk distance of the individual subjects were at the 9th, 13th, and 18th month. Oxygenation was stable, and no side effects were observed. We suggest from this experience that in clinical trials of PH in COPD, a follow-up of 16 weeks might cause underestimation of the treatment effects.
Topics: Aged; Antihypertensive Agents; Atrial Fibrillation; Bosentan; Comorbidity; Coronary Artery Disease; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Sulfonamides; Treatment Outcome; Vasoconstriction; Vasoconstrictor Agents
PubMed: 23258580
DOI: 10.4187/respcare.02058 -
International Journal of... 2010Raynaud?s phenomenon (RP) and cutaneous fibrosis are the distinctive manifestations of scleroderma, in which Endothelin-1 plays a fundamental pathogenetic role....
Bosentan treatment for Raynauds phenomenon and skin fibrosis in patients with Systemic Sclerosis and pulmonary arterial hypertension: an open-label, observational, retrospective study.
Raynaud?s phenomenon (RP) and cutaneous fibrosis are the distinctive manifestations of scleroderma, in which Endothelin-1 plays a fundamental pathogenetic role. Bosentan, an Endothelin-1 receptor antagonist used for the treatment of pulmonary arterial hypertension, retards the beginning of new sclerodermic digital ulcers (DU). This open-label, observational, retrospective study verified the effect of Bosentan on RP and skin fibrosis in sclerodermic outpatients affected by pulmonary arterial hypertension without DU. Fourteen subjects (13 women, 1 man; mean age 60 ± 7.5 years; ten with limited and four with diffuse scleroderma) were observed at baseline (T0) and after four (T1), twelve (T2), twenty-four (T3) and forty-eight (T4) weeks during treatment with Bosentan. They were evaluated for daily quantity and duration of RP attacks and skin thickness (using modified Rodnan total skin score, MRSS). Videocapillaroscopic evaluation was performed at T0 and T4. Bosentan decreased significantly the number and duration of RP attacks, beginning at T2 (p<0.05). Videocapillaroscopy showed significant improvement of microcirculatory patterns at T4 (p<0.05). MRSS decreased throughout the study, reaching the statistical significance at T3 and T4 (p<0.01) in the whole cohort. The present data suggest that Bosentan is effective in stabilizing the microcirculation involvement and in improving skin fibrosis irrespective of scleroderma patterns.
Topics: Aged; Bosentan; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Fibrosis; Humans; Hypertension, Pulmonary; Male; Middle Aged; Raynaud Disease; Retrospective Studies; Scleroderma, Systemic; Skin; Sulfonamides
PubMed: 21244767
DOI: 10.1177/039463201002300422 -
Respiration; International Review of... 2017Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or...
BACKGROUND
Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH).
OBJECTIVE
The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments.
METHODS
PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations. Concentrations were normalized considering dose and time from last medication intake and presented as multiples of the expected mean (MoM) of the respective monotherapies.
RESULTS
A total of 125 PAH patients (84 female, 41 male, 57% idiopathic/heritable) were included. Sildenafil and tadalafil concentrations were lowest in combination with bosentan (MoM 0.44 ± 0.42, 95% confidence interval [CI] 0.30-0.57, and MoM 0.89 ± 0.53, 95% CI 0.50-1.28, respectively) compared to the combination with ambrisentan (MoM 1.3 ± 0.97, 95% CI 0.86-1.73, and MoM 1.67 ± 0.63, 95% CI 1.40-1.94, respectively) and macitentan (MoM 1.16 ± 0.87, 95% CI 0.86-1.46, and MoM 1.59 ± 0.99, 95% CI 0.80-2.38, respectively). The combination of sildenafil and bosentan led to more than twice the expected bosentan concentrations in 53.8%. Patients switching from sildenafil-bosentan to macitentan showed a significant increase in sildenafil concentrations (p < 0.001).
CONCLUSIONS
Only the combination with macitentan or ambrisentan led to targeted mean PDE-5i plasma concentrations and should therefore be preferred to combination with bosentan. Sildenafil-bosentan showed the strongest interaction, with low sildenafil and high bosentan concentrations. The study was not powered to analyze whether lower PDE-5i concentrations cause unsatisfying clinical response. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.
Topics: Adult; Aged; Bosentan; Case-Control Studies; Drug Interactions; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Tadalafil
PubMed: 28494463
DOI: 10.1159/000470916 -
Vascular Health and Risk Management 2008Endothelin receptor antagonism has emerged as an important therapeutic approach in pulmonary arterial hypertension (PAH). Bench to bedside scientific research has shown... (Review)
Review
Endothelin receptor antagonism has emerged as an important therapeutic approach in pulmonary arterial hypertension (PAH). Bench to bedside scientific research has shown that endothelin-1 (ET-1) is overexpressed in several forms of pulmonary vascular disease and may play an important pathogenetic role in the development and progression of PAH. Oral endothelin receptor antagonists (ERAs) improved exercise capacity, functional status, pulmonary hemodynamics, and delayed the time to clinical worsening in several randomized placebo-controlled trials. Two ERAs are currently approved by the US Food and Drug Administration: bosentan, a dual ERA for patients with class III and IV PAH, and ambrisentan, a selective ERA for patients with class II and III PAH. Sitaxsentan, another selective ERA, has been approved in Europe, Canada, and Australia. The objective of this review is to evaluate the available evidence describing the pharmacology, efficacy, safety, and tolerability, and patient-focused perspectives regarding the different types of endothelin receptor antagonists. Ongoing and forthcoming randomized trials are also highlighted including the approach of combining this class of drugs with other drugs that target different cellular pathways believed to be etiologically important in PAH.
Topics: Animals; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Patient Compliance; Patient Satisfaction; Phenylpropionates; Pyridazines; Quality of Life; Receptors, Endothelin; Sulfonamides; Thiophenes; Treatment Outcome
PubMed: 19183742
DOI: 10.2147/vhrm.s2270 -
British Journal of Clinical Pharmacology Jan 2014The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the... (Clinical Trial)
Clinical Trial
AIMS
The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination.
METHODS
We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14.
RESULTS
Clarithromycin significantly increased bosentan area under the plasma concentration-time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance.
CONCLUSIONS
Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary.
Topics: Adult; Anti-Anxiety Agents; Bosentan; Clarithromycin; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Endothelin Receptor Antagonists; Female; Genotype; Healthy Volunteers; Humans; Liver-Specific Organic Anion Transporter 1; Male; Midazolam; Organic Anion Transporters; Sulfonamides
PubMed: 23738582
DOI: 10.1111/bcp.12177 -
BMC Pulmonary Medicine Feb 2024The data on bosentan were lacking for the treatment of exercise-induced elevation of pulmonary artery pressure (eePAP) or less severe PH in COPD. This study was... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical course of COPD patients with exercise-induced elevation of pulmonary artery pressure or less severe pulmonary hypertension presenting with respiratory symptoms and the impact of bosentan intervention-prospective, single-center, randomized, parallel-group study.
BACKGROUND
The data on bosentan were lacking for the treatment of exercise-induced elevation of pulmonary artery pressure (eePAP) or less severe PH in COPD. This study was conducted to investigate long-term efficacy and safety of bosentan for the treatment of eePAP or less severe PH in COPD.
METHODS
COPD patients diagnosed at this hospital as having COPD (WHO functional class II, III or IV) with eePAP or less severe PH whose respiratory symptoms were stable but remained and gradually progressed even after COPD therapy were randomly assigned in a 1:1 ratio to receive either bosentan or no PH treatment for two years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right heart catheterization (RHC), and other parameters.
RESULTS
A total of 29 patients who underwent RHC for detail examination were enrolled in the current study between August 2010 and October 2018.No death occurred in drug-treated group (n = 14) for 2 years; 5 patients died in untreated group (n = 15). Significant differences were noted between the 2 group in hospital-free survival (686.00 ± 55.87 days vs. 499.94 ± 53.27 days; hazard ratio [HR], 0.18; P = 0.026) and overall survival (727 days vs. 516.36 ± 55.38 days; HR, 0.095; P = 0.030) in all causes of death analysis, but not in overall survival in analysis of respiratory-related death. Bosentan was not associated with increased adverse events including requiring O inhalation.
CONCLUSIONS
This study suggested that the prognosis for COPD patients with eePAP or less severe PH presenting with respiratory symptoms was very poor and that bosentan tended to improve their prognosis and suppress ADL deterioration without worsening respiratory failure.
TRIAL REGISTRATION
This study was registered with UMIN-CTR Clinical Trial as UMIN000004749 . First trial registration at 18/12/2010.
Topics: Humans; Bosentan; Hypertension, Pulmonary; Pulmonary Artery; Activities of Daily Living; Prospective Studies; Endothelin Receptor Antagonists; Sulfonamides; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency; Disease Progression; Antihypertensive Agents; Treatment Outcome
PubMed: 38368315
DOI: 10.1186/s12890-024-02895-0 -
Clinical and Translational Science Feb 2016To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with... (Clinical Trial)
Clinical Trial
To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.
Topics: Adult; Bosentan; Drug Therapy, Combination; Exercise; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pyridazines; Sildenafil Citrate; Sulfonamides
PubMed: 26756977
DOI: 10.1111/cts.12382 -
Clinical Pharmacokinetics Feb 2022Tadalafil 40 mg once daily is approved for adult patients with pulmonary arterial hypertension (PAH). To investigate and potentially fulfill an unmet need in pediatric... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tadalafil 40 mg once daily is approved for adult patients with pulmonary arterial hypertension (PAH). To investigate and potentially fulfill an unmet need in pediatric patients with PAH, pharmacokinetic (PK) data were explored in a pediatric phase Ib/II study and pooled with prior phase III (pulmonary arterial hypertension and response to tadalafil [PHIRST-1]) adult data to develop the first population PK model for tadalafil in pediatric patients with PAH.
METHODS
H6D-MC-LVIG (NCT01484431) was an open-label, multicenter, multiple ascending dose study in pediatric patients with PAH, while PHIRST-1 was a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel design study in adults with PAH who received one of five treatments (tadalafil 2.5, 10, 20, or 40 mg, or placebo orally, once daily). PK data from the studies were pooled to develop a pediatric population PK model for tadalafil that characterized relationships among dose, exposure, and the effects of covariates with an aim to develop a population PK model that could simulate concentration-time profiles and assess exposure-matched dosing strategies in a pediatric PAH population.
RESULTS
In line with the observed data, modeling and simulation demonstrated that the doses studied in the pediatric population produced area under the concentration-time curves (AUCs) within the range of those associated with improved exercise ability in adults with PAH. The analyses included 1430 observations from 305 adult patients (PHIRST-1: 69 males and 236 females, 1102 observations) and 19 pediatric patients (LVIG: 6 males and 13 females, 328 observations) who received tadalafil once daily at different dose levels. The best-fit base model retained an effect of weight on apparent volume of distribution (V/F), fixed to the allometric scaling value of 1, and did not include an effect of weight on apparent clearance (CL/F). Other covariate effects were that bosentan increased CL/F, V/F decreased with decreasing body weight, and bioavailability (F) decreased with increasing dose and decreasing age. The PK model reliably predicted the observed concentrations and overall variability evident from the overlap of the individual observed concentrations with the distributions of simulated concentrations.
CONCLUSIONS
A one-compartment model parameterized in terms of F, absorption rate constant, CL/F, and V/F described the data well. The model demonstrated that plasma tadalafil concentrations in pediatric patients aged 2 to < 18 years were similar to those in adults at similar doses, and confirmed that dosing of 40 mg once daily in pediatric patients with a bodyweight ≥ 40 kg, and a dose of 20 mg once daily in patients with a body weight < 40 kg and aged ≥ 2 years are suitable for phase III evaluation.
TRIAL REGISTRATION NUMBER (DATE OF REGISTRATION)
LVIG: ClinicalTrials.gov identifier: NCT01484431 (2 December 2011). PHIRST-1: ClinicalTrials.gov identifier: NCT00125918 (2 August 2005).
Topics: Adult; Area Under Curve; Body Weight; Bosentan; Child; Female; Humans; Male; Pulmonary Arterial Hypertension; Tadalafil
PubMed: 34379314
DOI: 10.1007/s40262-021-01052-8 -
British Journal of Clinical Pharmacology Jun 2002The present study was conducted to characterize the single- and multiple-dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
AIMS
The present study was conducted to characterize the single- and multiple-dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a possible pharmacokinetic interaction with ketoconazole.
METHODS
In a randomized, two-way crossover study, 10 healthy male subjects received treatments A and B. Treatment A consisted of a single dose of 62.5 mg bosentan on day 1 followed by 62.5 mg twice daily for 5.5 days. Treatment B consisted of bosentan (62.5 mg twice daily) for 5.5 days plus concomitant ketoconazole (200 mg once daily) for 6 days. Plasma concentrations of bosentan and its three metabolites were measured on days 1 and 7 of treatment A and on day 6 of treatment B.
RESULTS
Bosentan was absorbed and eliminated with a tmax of 4.5 h (range 3.5-6.0 h) and a t(1/2) of 5.4 h (95% CI; 4.5, 6.6). Upon multiple dosing, the exposure to bosentan was reduced by 33% without change in tmax and t(1/2). Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1- (95% CI; 1.5, 2.7) and 2.3-fold (95% CI; 1.8, 2.9), respectively. Exposure to the metabolites was low and represented less than 25% of that to bosentan both after single and multiple doses. In the presence of ketoconazole, formation of the metabolites was inhibited.
DISCUSSION
The multiple-dose pharmacokinetics of bosentan are consistent with the phenomenon of auto-induction. In the presence of CYP3A4 inhibitors, bosentan concentrations may be increased 2-fold.
Topics: Adult; Antifungal Agents; Antihypertensive Agents; Area Under Curve; Bosentan; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Administration Schedule; Drug Interactions; Humans; Ketoconazole; Male; Sulfonamides
PubMed: 12047483
DOI: 10.1046/j.1365-2125.2002.01608.x