Macitentan In Patients Research Articles

Real-world effectiveness and safety of macitentan in patients with pulmonary artery hypertension: a multicenter, retrospective, observational study in China

Background Macitentan, either as monotherapy or part of combination therapy, improved clinical outcomes in patients with pulmonary artery hypertension (PAH) in clinical trials. Evidence on the effectiveness and safety of macitentan administered in real-world clinical practice in China is limited. Methods This real-world, retrospective, multicenter chart review study was conducted at seven hospitals in China. Adult patients with a diagnosis of PAH who initiated macitentan and had medical assessments at 3–7 months after macitentan initiation were included. The primary outcomes were changes in the World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)/B-type natriuretic peptide from baseline to first follow-up visit (months 3–7). Serious adverse events (SAEs) and adverse drug reactions (ADRs) of macitentan were collected. Results From 30 August 2021 to 31 March 2022, 214 eligible patients were included in the safety analysis set and 105 patients were included in the analysis of effectiveness. At the first follow-up visit compared with baseline, significant changes in WHO-FC were observed (p = .04), 93.5% patients had their WHO-FC improved (25.8%) or maintained (67.7%). 6MWD changed by a mean (standard deviation [SD]) of 45.0 (81.4) meters (p < .001), with 94.7% having their 6MWD improved (34.7%) or maintained (60.0%). The mean (SD) of NT-proBNP decreased from 1667.4 (3233.0) ng/L to 1090.0 (2230.1) ng/L (p < .001). In the safety analysis set, 24 (11.2%) patients experienced at least one ADR and/or SAE. ADRs and SAEs were reported in 11 (5.1%) and 18 (8.4%), respectively. No deaths or unexpected safety events were observed. Conclusion This study provided real-world evidence on the clinical benefits and good tolerance of macitentan in Chinese patients with PAH treated in routine clinical practice.

Macitentan in Adults with Sickle Cell Disease and Pulmonary Hypertension: A Proof-of-Concept Study

Pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with a mortality rate of 37%. There is an upregulation of adhesion molecules which leads to the expression of endothelin-1, a potent vasoconstrictor. A prospective, descriptive study was done to determine the safety and efficacy of macitentan in patients with SCD and PH. Continuous variables were reported as mean ± SEM or percentage where appropriate. We screened 13 patients and recruited five. All five patients were adults. Data were analyzed as appropriate by student t - test. Statistical significance was assumed at p &lt; 0.05. Baseline pulmonary hemodynamics obtained by right heart catheterization and systemic hemodynamics were (± SEM): mean pulmonary artery pressure (MPAP) 32 ± 8 mmHg, right atrial pressure (RAP) 9 ± 4 mmHg, pulmonary vascular resistance (PVR) 257 dynes-sec/cm5 and CI 3·7 ± 0.39 l/m2. Of all parameters, only PVR and 6-min walk distance changed significantly. For the group, MPAP decreased by 15.6%, PVR by 22.5% and RAP by 25.5%. The 6-minute walk distance increased over sixteen weeks except in Patient 4 who had a 3% decrease. The mean walk distance increased in the total distance, from 464 ± 158 meters to 477 ± 190 meters (p .123). In four patients, the adverse events were mild to moderate and did not lead to study drug discontinuation. Significant improvement in pulmonary hemodynamics and exercise capacity in patients with SCD-related pulmonary arterial hypertension. We found that macitentan was safe and well tolerated.

Macitentan in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease (CTD-PAH): Real-World Evidence from the Combined OPUS/OrPHeUS Dataset.

Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. gov Graphical abstract available for this article.

Safety of Macitentan for the Treatment of Portopulmonary Hypertension: Real-World Evidence from the Combined OPUS/OrPHeUS Studies.

Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset. OPUS was a prospective, US, multicenter, observational drug registry (April 2014-June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013-March 2017). Additional information regarding patients' liver disease was retrospectively collected for patients with PoPH in OPUS. The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan-Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events. There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article. OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. gov .

Benefits of Macitentan in Patients with Pulmonary Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis aimed to determine the efficacy of macitentan in patients with pulmonary hypertension (PH). A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of PH with macitentan, compared with placebo or blank, were reviewed. Studies were pooled to weighted mean differences (WMDs) and risk ratios (RRs), with 95% confidence intervals (CIs). Six RCTs (enrolling 1,003 participants) met the inclusion criteria. Macitentan showed significant effects on 6-min walk distance (6MWD) (WMD 12.06 m, 95% CI 2.12 to 21.99 m), pulmonary vascular resistance (PVR) (WMD -186.51 dyn·s/cm-5, 95% CI -232.72 to -140.29 dyn·s/cm-5), mean pulmonary artery pressure (mPAP) (WMD -3.20 mmHg, 95% CI -5.93 to -0.47 mmHg), N-terminal pro-brain natriuretic peptide (NT-proBNP) (WMD -232.47 ng/L, 95% wCI -318.22 to -146.72 ng/L), and cardiac index (WMD 0.39 L/min/m2, 95% CI 0.20 to 0.58 L/min/m2). Macitentan significantly improved 6MWD, PVR, mPAP, NT-proBNP, and cardiac index in patients with PH. Macitentan should be further validated in patients with PH.

Long-term safety of macitentan in patients with pulmonary hypertension: A meta-analysis of randomised controlled trials.

Macitentan has demonstrated its effectiveness in patients with pulmonary hypertension (PH), but its safety, especially for long-term use, needs to be further explored. This systematic review and meta-analysis aimed to determine the safety of long-term use of macitentan in patients with PH. A systematic search was made of PubMed, Embase, Cochrane Library and clinicaltrials.gov, without language restrictions. Randomised controlled trials (RCTs) on treatment of PH with macitentan, compared with placebo, were reviewed. Estimated effects of included studies were pooled as risk ratios (RRs), with 95% confidence intervals (CIs). Six RCTs (enrolling 1003 participants) met the inclusion criteria. Anaemia (RR 3.86, 95% CI 2.05-7.30), headache (RR 1.52, 95% CI 1.02-2.26) and bronchitis (RR 2.24, 95% CI 1.30-3.87) were more frequent in the macitentan groups. There was no statistically significant difference in the proportion of patients with at least one adverse event (AE) or serious adverse event (SAE), AEs leading to discontinuation of study treatment, all-cause death, right ventricular failure (RVF) and peripheral oedema between the two groups. The long-term use of macitentan is safe for patients with PH, although with a higher risk of anaemia, headache and bronchitis.

The Transition From Ambrisentan to Macitentan in Patients With Pulmonary Arterial Hypertension: A Real-word Prospective Study.

Background: In a long-term event-driven trial, macitentan has demonstrated beneficial time to clinical worsening in patients with pulmonary arterial hypertension (PAH) and reduced PAH-related hospitalization rates compared with placebo. Macitentan is the most recently approved endothelin receptor antagonist (ERA) and is the first ERA that has shown efficacy for morbidity and mortality in PAH patients; therefore, patients and physicians may consider converting treatment from ambrisentan to macitentan. Our study evaluated the safety, efficacy, and quality of life in PAH patients transitioning from ambrisentan to macitentan. Methods: This was a real-world, prospective study with a 12-month follow-up. PAH patients who had received stable doses of ambrisentan for over 3 months, were within the World Health Organization Functional Class II/III, and 6-min walk distance ≥ of 250 m were enrolled. The study included a screening period, followed by a transition phase, after which patients entered the long-term follow-up. Clinical data and treatment satisfaction outcomes were collected to assess and monitor the safety and efficacy of the transition. The trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn; No. ChiCTR2000034898). Results: One hundred and fifty-seven enrolled PAH patients completed the transition. All criteria for continuous treatment transition were met by 145 patients (92.4%). Results showed improvements in exercise capacity, cardiac function, and hemodynamics compared with baseline. During the process, 4 patients discontinued macitentan due to adverse events. There was no statistical difference in the overall incidence of adverse events before and after the transition. Conclusion: Transition to macitentan from ambrisentan was successful and well-tolerated by PAH patients, and was associated with greater efficacy and satisfaction.

First Results of Soprano: Macitentan in Patients (pts) with Pulmonary Hypertension (PH) Post-Left Ventricular Assist Device (LVAD) Implantation

<h3>Purpose</h3> To assess the efficacy and safety of macitentan in pts with PH post-LVAD. <h3>Methods</h3> SOPRANO (NCT02554903) was a double-blind, randomized, study of macitentan 10 mg once-daily vs placebo. Pts were ≥18 years with LVAD implanted within 90 days prior to randomization, had mean pulmonary arterial pressure (mPAP) ≥25 mmHg, pulmonary artery wedge pressure (PAWP) ≤18 mmHg and pulmonary vascular resistance (PVR) >3 Wood units (WU). The primary endpoint was change in PVR at week 12 of therapy from baseline. <h3>Results</h3> Fifty-seven pts were randomized: macitentan (n=28) or placebo (n=29). Baseline pt demographics and characteristics were well balanced. Baseline PVR (mean [SD]) was 4.3 [0.9] WU (macitentan) and 4.3 [1.3] WU (placebo). At week 12, mean PVR decreased to 58.5% (macitentan) and to 75.5% (placebo) of baseline. Mean placebo-corrected reduction in PVR of macitentan was 26.1% (95% CI: 58.0, 94.3; p=0.0158). Predefined secondary endpoints, notably including changes in PAWP, were not significantly different with macitentan vs placebo (Table). Another relevant hemodynamic parameter, transpulmonary gradient, significantly decreased with macitentan vs placebo (p=0.0499). The incidence of treatment adverse events (TAEs) was 21.4% (macitentan) and 24.1% (placebo); no TAEs occurred in >1 patient in the macitentan arm. AEs of interest included edema, anemia and hypotension: reported in 7 (25.0%), 3 (10.7%), and 4 (14.3%) pts on macitentan (mostly mild-moderate) and in 5 (17.2%), 2 (6.9%) and 1 (3.6%) pts on placebo, respectively. Two pts on macitentan and 1 pt on placebo discontinued for treatment-related AEs. <h3>Conclusion</h3> In the first prospective, multicenter, randomized controlled trial of pulmonary vasodilators in the early post-LVAD population, macitentan significantly reduced PVR and was well tolerated. The impact of macitentan on post-LVAD exercise capacity and RV failure warrants further study.

Simultaneous LC-MS analysis of plasma concentrations of sildenafil, tadalafil, bosentan, ambrisentan, and macitentan in patients with pulmonary arterial hypertension.

Phosphodiesterase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERAs) are standard therapies for pulmonary arterial hypertension (PAH). The inter-individual variability of these pharmacokinetics is reported remarkably large, and therapeutic drug monitoring (TDM) can be useful to improve the likelihood of the desired therapeutic and safety outcomes. This study aimed to develop a LC-MS method to determine the concentrations of five PAH drugs (PDE-5 inhibitors: sildenafil and tadalafil, ERAs: bosentan, macitentan, and ambrisentan) from plasma samples using a simple process followed by a single mass spectrometric run, and to validate this approach through pharmacokinetic analyses in patients. A solid extraction method was used for sample preparation of the drugs from human plasma. The total run time for a single injection was within 10 min. The calibration curves for all drugs were linear, and the lower limits of quantitation were 1 (sildenafil), 2 (tadalafil), 5 (ambrisentan), and 10 ng/mL (bosentan, macitentan). The accuracy and precision values suggested that the assay had high accuracy and reliability. To prove the utility of this method, the plasma concentrations of the five PAH drugs were determined after their oral administration to nine PAH patients.

Outcome Study Assessing a 75 Milligrams (mg) Dose of Macitentan in Patients With Pulmonary Arterial Hypertension

Outcome Study Assessing a 75 Milligrams (mg) Dose of Macitentan in Patients With Pulmonary Arterial Hypertension

Evolution of Patients with Pulmonary Arterial Hypertension Starting Macitentan After the Discontinuation of Other Endothelin-Receptor Antagonists: Results of a Retrospective Study.

Macitentan is the latest endothelin-receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), presenting enhanced properties over previous ERAs. We describe the clinical and echocardiographic evolution of patients with PAH who started macitentan after discontinuing bosentan/ambrisentan. This was a retrospective series of patients with different etiologies who started macitentan after the suspension of other ERAs under routine clinical practice at five Spanish hospitals. World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and cardiac imaging data were collected and described at baseline (before macitentan initiation) and after 3, 6, and 12months, when available. In total, 12 patients (ten women; mean age 65.63 ± 13.27years) were observed. At baseline, most patients were receiving concomitant PAH medications, and five patients were classed as WHO-FC III. After 3months of macitentan treatment, WHO-FC had improved in four patients, 6MWD increased in eight patients, and NT-proBNP levels and right atrial area were lowered in seven and eight patients, respectively. Similar results were observed after 6 and 12months. Macitentan was well-tolerated, with no PAH hospitalizations, septostomies, transplants, or deaths registered. Our results suggest that switching to macitentan in patients with PAH who discontinued bosentan/ambrisentan was well-tolerated and effective. Further studies are needed to confirm these observations.

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects.

BackgroundMacitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug–drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH.ObjectiveTwo Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan.MethodsHealthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0–t), the AUC from zero to infinity (AUC0–∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat’s metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout.ResultsNinety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80–1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs.ConclusionsMacitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects.EudraCT numbers: 2017–003095–31 and 2017–003502–41.

Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial

No dedicated randomised clinical trials have evaluated therapies for pulmonary arterial hypertension in patients with portopulmonary hypertension. The endothelin receptor antagonist macitentan has demonstrated long-term efficacy in pulmonary arterial hypertension with a good hepatic safety profile. We aimed to evaluate efficacy and safety of macitentan in patients with portopulmonary hypertension. PORTICO was a phase 4 study done in 36 centres in seven countries, consisting of a 12-week double-blind period (randomly assigned 1:1 to macitentan 10 mg or placebo once daily) followed by a 12-week open-label period. Adults (≥18 years) with portopulmonary hypertension, a 6-minute walk distance of 50 m or more, and with pulmonary vascular resistance of 320 dyn·s·cm-5 or more without severe hepatic impairment (Child-Pugh class C or model for end-stage liver disease score ≥19) were eligible. The primary endpoint was pulmonary vascular resistance at week 12, expressed as ratio of baseline in the full analysis set. Safety was assessed throughout. This trial is registered at ClinicalTrials.gov, number NCT02382016. Between June 23, 2015, and July 28, 2017, 85 patients were randomly assigned to macitentan (n=43) or placebo (n=42). At baseline, 54 (64%) were receiving background therapy for pulmonary arterial hypertension. Most patients were WHO functional class II (50, 59%) or III (33, 39%) with a mean 6-minute walk distance of 384·5 m (SD 103·9). At week 12, the geometric mean ratio of baseline pulmonary vascular resistance was 0·63 (95% CI 0·58-0·67) in the macitentan group and 0·98 (95% CI 0·91-1·05) in the placebo group, corresponding to a ratio of geometric mean for pulmonary vascular resistance of 0·65 (95% CI 0·59-0·72, p<0·0001), which in turn represented a 35% (95% CI 28-41) reduction in pulmonary vascular resistance with macitentan versus placebo. During the double-blind period, 36 (84%) macitentan-treated and 33 (79%) placebo-treated patients had adverse events, and nine (21%) and six (14%), had serious adverse events. Four (9%) macitentan-treated patients had an adverse event leading to discontinuation versus none in the placebo group. The most frequent adverse event during the double-blind period was peripheral oedema (11 [26%] in the macitentan group and five [12%] in the placebo group). Macitentan significantly improved pulmonary vascular resistance in portopulmonary hypertension patients, with no hepatic safety concerns. Actelion Pharmaceuticals Ltd.

Treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Real-World Experience with Macitentan

Purpose To describe real-world experience with macitentan in patients with CTEPH enrolled in the OPsumit® USers registry (OPUS; NCT02126943). Methods OPUS is an ongoing, long-term, prospective, US, multicenter, observational drug registry of patients newly treated with macitentan. This subgroup analysis describes the clinical characteristics, treatment patterns and safety of macitentan in CTEPH patients in OPUS. Results As of April 2018, OPUS included 45 CTEPH patients with follow-up data. Of these, 35 patients were not candidates for pulmonary endarterectomy (PEA), 7 had persistent pulmonary hypertension (PH) post-PEA, 1 had persistent PH post-balloon pulmonary angioplasty (BPA), 1 was bridging to PEA/BPA and the information was not known for 1 patient. At enrollment, median age (range) was 67 (18-87) years; 64.4% were female. Median (Q1, Q3) time from CTEPH diagnosis was 15.6 (7.8, 40.4) months. Use of macitentan in double or triple combination therapy regimens is shown in the Table for CTEPH patients and patients with pulmonary arterial hypertension (PAH) enrolled in OPUS. In CTEPH, macitentan was initiated as monotherapy in 13 (28.9%) patients, as double combination therapy in 31 (68.9%) patients, and as triple combination therapy in 1 (2.2%) patient. Macitentan was combined with riociguat in 80.6% of patients receiving double combination therapy. Median (Q1, Q3) exposure to macitentan was 9.9 (2.5, 19.9) months. At least 1 adverse event was experienced by 32 (71.1%) patients; the most common were dyspnea (15.6%), dizziness (11.1%) and pneumonia (11.1%). One patient died during the follow-up period. Conclusion OPUS provides insight into real-world use of macitentan. When used in CTEPH, macitentan was received in combination with other PAH therapies in approximately 70% of patients, and most frequently combined with riociguat. There were no unexpected safety findings in CTEPH patients.

Patient Characteristics and Treatment Patterns with Macitentan in Pulmonary Arterial Hypertension: Insights from the OPUS Registry

Purpose To describe the real-world use and safety profile of macitentan in patients with pulmonary arterial hypertension (PAH) enrolled in the OPsumit® USers registry (OPUS; NCT02126943). Methods OPUS is an ongoing long-term, prospective, multicenter, observational drug registry of patients newly treated with macitentan in the USA. Patient characteristics, treatment patterns, safety of macitentan and survival were analyzed for PAH patients. Results As of April 2018, OPUS included 1455 PAH patients with follow-up data. At enrollment, median (range) age was 62 (13-92) years and 75.2% were female. The median (Q1, Q3) time from PAH diagnosis was 6.2 (1.5, 37.0) months. WHO functional class (FC) was assessed in 1062 patients, 39.3% were in FC I/II and 60.7% in FC III/IV; median (Q1, Q3) 6-minute walk distance, assessed in 620 patients, was 305 (206, 383) meters. Use of macitentan in double or triple combination therapy regimens is shown in the Table. Median (Q1, Q3) exposure to macitentan was 11.6 (3.9, 22.2) months and macitentan was discontinued by 28.7% of patients, with adverse events (AEs) as the most common reason. At least 1 AE was experienced by 1076 (74.0%) patients; the most common were dyspnea (18.2%), headache (9.5%) and peripheral edema (8.8%). In total, 485 (33.3%) patients experienced ≥1 hospitalization. The Kaplan-Meier survival estimates (95% CI) were 91% (90, 93) at 12 months and 84% (82, 87) at 24 months. Conclusion OPUS represents the largest cohort of patients newly treated with macitentan, providing insight into macitentan use in the real-world. These analyses show that macitentan is most commonly initiated as monotherapy or in combination with a phosphodiesterase type 5 inhibitor in PAH. The safety profile of macitentan in OPUS is consistent with that observed in clinical trials.

A novel, rapid and sensitive UPLC-MS/MS method for the determination of macitentan in patients with pulmonary arterial hypertension.

Macitentan is an endothelin receptor antagonist commonly used in the treatment of pulmonary arterial hypertension (PAH). A novel, rapid, simple and sensitive UPLC-MS/MS method was developed and validated for pharmacokinetic study and the determination of macitentan in PAH patients. Macitentan and bosentan, which are used as internal standards, were detected using atmospheric pressure chemical ionization in positive ion and multiple reaction monitoring mode by monitoring the mass transitions m/z 589.1 → 203.3 and 552.6 → 311.5, respectively. Chromatographic separation was performed on a reverse-phase C18 column (5 μm, 4.6 × 150 mm) with an isocratic mobile phase, which consisted of water containing 0.2% acetic acid-acetonitrile (90:10, v/v) at a flow rate of 1 mL/min. Retention times were 1.97 and 1.72 min for macitentan and IS, respectively. The calibration curve with high correlation coefficient (0.9996) was linear in the range 1-500 ng/mL. The lower limit of quantitation and average recovery values were determined as 1 ng/mL and 89.8%, respectively. This method is the first UPLC-MS/MS method developed and validated for the determination of macitentan from human plasma. The developed analytical method was fully validated for linearity, selectivity, specificity, accuracy, precision, sensitivity, stability, matrix effect and recovery according to US Food and Drug Administration guidelines. The developed method was applied successfully for pharmacokinetic study and the determination of macitentan in PAH patients.

Macitentan in daily clinical practice: A single centre, 1-year experience

The effectiveness and safety of macitentan, a dual endothelin-receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), were shown in an extensive clinical trial oriented towards morbidity and mortality events. Our aim was to describe a single centre's experience of the utilization of macitentan in patients with PAH in clinical practice settings. Thirteen patients with different aetiologies and previous PAH treatments were studied. After 12 months of macitentan treatment, 11 patients improved their functional class (FC), all patients improved their 6-minute walk distance (6MWD) test, and 10 patients lowered their NT-proBNP plasma levels. Additionally, cardiac imaging parameters were also improved. No cases resulted in hospitalization, septostomy, transplant or death.

Modeling of pharmacokinetics, efficacy, and hemodynamic effects of macitentan in patients with pulmonary arterial hypertension

BackgroundMacitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. MethodsThe pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. ResultsSex, age, and body weight influenced the PK to a statistically significant extent. Model-based simulations showed that these variables are clinically not relevant. Concomitant use of PAH medication (PDE-5 inhibitors) did not influence macitentan trough concentration to a relevant extent.Efficacy and hemodynamics showed clear differences from placebo for macitentan concentrations on 3 and 10 mg with consistent superior effects for 10 mg. After 6 months, PAH patients showed model-predicted 6-min walk distance (6-MWD) improvements of 1.0 m on placebo compared to 29.8 and 34.1 m on 3 and 10 mg of macitentan, respectively. Higher macitentan concentrations were associated with reductions in pulmonary vascular resistance (PVR), mean right atrial and pulmonary arterial pressure, and total pulmonary resistance (TPR) and increases in cardiac index (CI) and mixed venous oxygen saturation. Statistical significance was determined for PVR, TPR, and CI but not for 6-MWD. In addition, PVR showed more pronounced differences between active treatment and placebo than 6-MWD. ConclusionsModeling identified statistically significant inter-patient differences; simulations to assess the magnitude of the effects permitted clinical judgment. The same approach will allow for extrapolation to children. Hemodynamic markers might be better markers of treatment effects than 6-MWD. Trial registrationThe SERAPHIN study and its open-label extension are registered with ClinicalTrials.gov with identifiers NCT00660179 (https://www.clinicaltrials.gov/ct2/show/NCT00660179) and NCT00667823 (https://clinicaltrials.gov/ct2/show/NCT00667823) and with EudraCT with identifiers 2007-002440-14 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002440-14) and 2007-003694-27 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-003694-27).

OPUS Registry: Treatment Patterns and Safety of Macitentan in Patients With Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (PAH-SSc)

OPUS Registry: Treatment Patterns and Safety of Macitentan in Patients With Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (PAH-SSc)

P5462Evaluation of macitentan in patients with Eisenmenger syndrome: results from the randomised controlled MAESTRO study

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