Macitentan 10mg tablets

Chronic thromboembolic pulmonary hypertension (CTEPH) is a major risk for pulmonary hypertension with poor prognosis. Limited data is available on the optimal treatment of choice. We aimed to comprehensively assess the efficacy and safety of CTEPH targeted therapies and update the evidence. We searched PubMed, Scopus, and the Cochrane library up to December 2023 to include randomized controlled trials comparing different therapies in patients with CTEPH. Primary outcomes were 6-minute walk distance (6 MWD), pulmonary vascular resistance (PVR), and mean pulmonary artery pressure (mPAP). While secondary outcomes were the mean right atrial pressure (mRAP), Borg dyspnea score, cardiac output (CO), cardiac index, adverse events, and all-cause mortality. Fourteen RCTs comprising 1047 patients were included in this network meta-analysis. Regarding 6 MWD, PADN (MD=113.59, 95% CI: 53.80; 173.39), BPA (MD=48.84, 95% CI: 27.99; 69.69), riociguat (MD=42.59, 95% CI: 22.01; 63.18), treprostinil (MD=41.60, 95% CI: 17.07; 66.13), and macitentan (MD=34.00, 95% CI: 3.50; 64.50) were favored compared to placebo. In terms of PVR, BPA (MD=-392.19, 95% CI: -571.77; -212.62), treprostinil (MD=-287.20, 95% CI: -475.63; -98.77), PADN (MD=-280.61, 95% CI: -506.69; -54.52), bosentan (MD=-176.00, 95% CI: -340.91; -11.09), and riociguat (MD=-171.61, 95% CI: -298.40; -44.81) displayed statistically significant results. Current therapeutic modalities are effective in terms of improving exercise capacity, pulmonary hemodynamics, and reducing adverse events and all-cause mortality. Overall, BPA and PADN were superior to all other targeted medications in the studied outcomes. • The optimal treatment modality for CTEPH is still controversial, with conflicting data in the literature. • Our meta-analysis of 14 RCTs showed that BPA and PADN were superior to all other treatment modalities to reduce the odds of mortality. • SUCRA values and treatment ranking list confirm the current findings. • This study can be a guide of recommending BPA and PADN as the approaches of choice in treating CTEPH. • These findings should be validated with large-volume RCTs with long-term outcomes.

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BACKGROUND: Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention. METHODS: In this randomized, double-blind, multicenter trial (SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]), we evaluated the effects of an endothelin receptor antagonist, macitentan, in patients with HF, left ventricular ejection fraction ≥40%, and pulmonary vascular disease. After a 4-week placebo run-in (to ensure clinical stability), followed by a 5-week single-blind macitentan run-in, patients who did not exhibit fluid retention were randomized to macitentan or placebo. The primary end point was change in NT-proBNP (N-terminal pro-B-type natriuretic peptide; baseline to 24 weeks); secondary end points included change in KCCQ (Kansas City Cardiomyopathy Questionnaire) clinical summary score (baseline to 24 weeks) and time to worsening HF by 52 weeks. RESULTS: Of 230 patients enrolled, 28 were excluded during the placebo run-in, 60 excluded during the macitentan run-in, and 142 were randomized. Macitentan had no effect on change in NT-proBNP (geometric mean ratio [macitentan/placebo], 1.02 [90% CI, 0.88–1.19]; P =0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, −3.5 [90% CI, −8.2 to +1.2]; P =0.22). Worsening HF occurred in 20 (28%) patients assigned to macitentan and 13 (18%) assigned to placebo (hazard ratio, 1.48 [90% CI, 0.83–2.67]; P =0.24). More macitentan-treated patients developed fluid retention (16 [23%] versus 10 [14%]) and cardiac adverse events (33 [46%] versus 22 [31%]) versus placebo. CONCLUSIONS: Despite a novel enrichment trial design to target pulmonary vascular disease and exclude treatment-related fluid retention in patients with HF and preserved/mildly reduced left ventricular ejection fraction, macitentan neither lowered NT-proBNP nor improved HF outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03153111 and NCT03714815.

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OBJECTIVES: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). METHODS: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. RESULTS: In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. CONCLUSIONS: The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

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AIMS: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities. METHODS AND RESULTS: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups. CONCLUSIONS: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups.

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• A rapid, cost-effective LC-MS/MS method was developed for simultaneous analysis of tadalafil and macitentan in rat plasma. • Chromatographic conditions were optimized using a Design of expert approach. • The method was validated according to regulatory guidelines. • Pharmacokinetic studies were assessed for tadalafil and macitentan. • A greenness assessment was conducted using several green and white chemistry approach. This study presents the development and validation of a sensitive LC-MS/MS method for the simultaneous quantification of tadalafil and macitentan in rat plasma, enabling detailed pharmacokinetic profiling following single-dose administration. Optimization of critical parameters, including organic phase composition (50% acetonitrile), flow rate (1.0 mL/min), and pH (3.2), was achieved using a Box-Behnken Design, ensuring accurate separation and quantification. The retention times were 4.13 min for tadalafil, 5.32 min for macitentan, and 7.89 min for the internal standard, ritonavir. The method adhered to regulatory validation guidelines, linearity was observed over a concentration range of 20 to 400 ng/mL for tadalafil and 5 to 100 ng/ml for macitentan, yielding correlation coefficients of 0.9997 and 0.9998, respectively, with limits of quantitation (LOQs) of 19.10 ng/mL for tadalafil and 4.21 ng/mL for macitentan. Precision, expressed as %CV, was consistently below 15% for both intra- and inter-day variability. Drug recovery exceeded 98%, and stability tests demonstrated robustness under various conditions, with %CV values remaining under 15%. Pharmacokinetic studies in male Wistar rats (tadalafil: 0.0033 mg/kg; macitentan: 0.0003 mg/kg) revealed distinct absorption and elimination profiles. Tadalafil exhibited a peak concentration (Cmax) of 164.2 ng/mL at 1.5 h, an AUC0–t of 806 ng·h/mL, and a half-life of 5 h, indicative of rapid clearance. In contrast, macitentan displayed a lower Cmax of 43.8 ng/mL at 2 h, an AUC0–t of 987 ng·h/mL, and a prolonged half-life of 15 h, suggesting sustained systemic exposure. These pharmacokinetic variations highlight the potential for tailored dosing strategies. Environmental assessment using green analytical chemistry tools confirmed the eco-friendly design of the method, characterized by reduced solvent consumption and low toxicity. This validated LC-MS/MS method provides a robust and sustainable analytical solution for preclinical pharmacokinetic studies, delivering reliable data to inform safe and effective dosing of tadalafil and macitentan.

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INTRODUCTION: 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. METHODS: 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). RESULTS: 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 279 m; 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 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). CONCLUSIONS: 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. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov Graphical abstract available for this article.

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INTRODUCTION: 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. METHODS: 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. RESULTS: The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58 years; 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. CONCLUSION: 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. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov .

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