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Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects.
Journal of clinical pharmacology, 2017Co-Authors: Milena Issac, Jasper Dingemanse, Patricia N SidhartaAbstract:Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (Ctrough ) of Macitentan and its active metabolite, ACT-132577, were obtained at steady state in 242 patients, indicating that mean Ctrough of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of Macitentan and its active metabolite, ACT-132577, a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN. A cross-study comparison showed that although Ctrough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for Macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (Cmax ) or area under the plasma concentration-time curve over a dosing interval (AUCτ ). Geometric mean ratios for Cmax and AUCτ were 1.08 and 1.22, respectively, for Macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to Macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.
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Pharmacokinetic and pharmacodynamic evaluation of Macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension
Expert opinion on drug metabolism & toxicology, 2015Co-Authors: Patricia N Sidharta, Stephan Krähenbühl, Jasper DingemanseAbstract:Introduction: Pulmonary arterial hypertension (PAH) is a chronic disorder of the pulmonary vasculature characterized by elevated mean pulmonary arterial pressure eventually leading to right-sided heart failure and premature death. Macitentan is an oral, once-daily, dual endothelin (ET)A and ETB receptor antagonist with high affinity and sustained receptor binding that was approved in the USA, Europe, Canada, and Switzerland for the treatment of PAH.Areas covered: This review discusses the pharmacokinetics (PK) and pharmacodynamics (PD) of Macitentan and its drug interaction potential based on preclinical and clinical data.Expert opinion: Up to date, Macitentan is the only registered treatment for PAH that significantly reduced morbidity and mortality as a combined endpoint in a long-term event-driven study. The safety profile of Macitentan is favorable with respect to hepatic safety and edema/fluid retention and may be better than that of other ET receptor antagonists such as bosentan and ambrisentan. The...
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Investigation of mutual pharmacokinetic interactions between Macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects
British journal of clinical pharmacology, 2014Co-Authors: Patricia N Sidharta, Paul L M Van Giersbergen, Michael Wolzt, Jasper DingemanseAbstract:Aim To study the mutual pharmacokinetic interactions between Macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects. Methods In this open-label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg Macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration−time profiles of Macitentan and its active metabolite ACT-132577 (treatments A and C) and sildenafil and its N-desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non-compartmentally. Results The pharmacokinetics of Macitentan were not affected by sildenafil. In the presence of sildenafil Cmax and AUCτ of the metabolite ACT-132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of Macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased Cmax and AUCτ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N-desmethylsildenafil were not affected by Macitentan. All treatments were well tolerated. Conclusion A minor, not clinically relevant, pharmacokinetic interaction was observed between Macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with Macitentan and sildenafil.
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Pharmacokinetic–Pharmacodynamic Relationships of Macitentan, a New Endothelin Receptor Antagonist, After Multiple Dosing in Healthy Korean Subjects
American Journal of Cardiovascular Drugs, 2014Co-Authors: Li Young Ahn, Jasper Dingemanse, Sung Eun Kim, Kyoung Soo Lim, In-jin JangAbstract:Background and objectives Macitentan is a novel dual endothelin (ET)-1 receptor antagonist to be used in patients with pulmonary arterial hypertension. This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of Macitentan after administration of multiple doses to healthy Korean male subjects. Methods A randomized, double-blind, placebo-controlled, multiple-ascending dose study was performed in 30 healthy male subjects receiving oral Macitentan (3, 10, or 30 mg) or placebo once daily for 10 days. Plasma concentrations of Macitentan, its active metabolite ACT-13277, and ET-1 were evaluated. Safety and tolerability measurements were conducted throughout the study. Results The concentration–time profile of Macitentan was characterized by slow absorption (median time to maximum plasma concentration [ t _max] 9–10 h) and slow elimination (mean elimination half-life [ t _½] 11–15 h). After repeated doses of 3, 10, and 30 mg of Macitentan over the course of 10 days, the peak concentration ( C _max) increased as the dose increased and the area under the plasma concentration–time curve during the dosing interval (AUC_ τ ) increased in a dose-proportional manner. Plasma concentrations showed approximately 1.5- to 1.9-fold accumulation on day 10 compared with day 1. ACT-132577 showed higher levels of exposure than Macitentan, its mean half-life was 46–48 h, and it accumulated 7- to 12-fold. Macitentan increased plasma ET-1 concentrations at all doses tested and was well tolerated and elicited no serious adverse events. Conclusion Multiple oral doses of 3, 10, and 30 mg of Macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations.
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Investigation of the Effect of Macitentan on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects
Clinical Drug Investigation, 2014Co-Authors: Patricia N Sidharta, Hartmut Dietrich, Jasper DingemanseAbstract:Background and Objectives Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of pulmonary arterial hypertension (PAH). Warfarin, an anticoagulant often prescribed to patients with PAH, has a narrow therapeutic index and is prone to potential interactions with drugs. This study assessed the effects of Macitentan on the pharmacokinetics and pharmacodynamics of single-dose warfarin in healthy subjects. Methods This was a randomised, open-label, single-centre, two-way crossover (treatment A followed by treatment B, or vice versa), phase I study in 14 healthy male subjects. Treatment A was a loading dose of Macitentan 30 mg on Day 1 followed by 10 mg once daily for 8 days, with a single 25 mg dose of warfarin on Day 4. Treatment B was a single dose of warfarin on Day 1. Blood samples were assessed for warfarin pharmacokinetics (R- and S-warfarin) and pharmacodynamics [international normalised ratio (INR) and factor VII]. Plasma trough concentrations of Macitentan and its active metabolite (ACT-132577) and the safety and tolerability of each treatment were also assessed. Results Plasma concentrations of R- and S-warfarin were similar in both treatment periods. Warfarin did not affect the mean trough plasma concentrations of Macitentan or ACT-132577. Macitentan did not affect the pharmacodynamics of warfarin; the mean INR and factor VII activity versus time profiles were similar with and without Macitentan. Conclusions The absence of effect of Macitentan on the pharmacokinetics and pharmacodynamics of a single dose of warfarin suggests that both drugs can be concomitantly administered without need for dose adjustment.
Patricia N Sidharta - One of the best experts on this subject based on the ideXlab platform.
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Bioequivalence of Macitentan and tadalafil given as fixed‐dose combination or single‐component tablets in healthy subjects
British journal of clinical pharmacology, 2020Co-Authors: Simon Grill, Patricia N Sidharta, Shirin Bruderer, Mariya Antonova, Susanne Globig, James Carlson, Armin Schultz, Denes CsonkaAbstract:Aims To demonstrate the bioequivalence of Macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of Macitentan and tadalafil in healthy subjects. Methods Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of Macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods. Results Bioequivalence of Macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies. Conclusion The FDC-2 tablet containing 10 mg/40 mg of Macitentan/tadalafil was bioequivalent to the free combination of 10 mg Macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.
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Relative bioavailability of a pediatric dispersible tablet and adult film-coated tablet of Macitentan in healthy volunteers.
Pharmacology research & perspectives, 2020Co-Authors: Patricia N Sidharta, Susanne Globig, Ivan Ulč, Radka Štěpánová, Denes CsonkaAbstract:To compare the pharmacokinetic (PK) properties of the pediatric dispersible tablet formulation of Macitentan and the adult film-coated tablet formulation of Macitentan in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover, Phase 1 study was conducted in 12 healthy adults. Subjects were randomized to one of the two possible treatment sequences A/B or B/A on Day 1 under fasted conditions. Treatment A was a single 10 mg dose of Macitentan (film-coated adult formulation) and Treatment B was a single 10 mg dose of Macitentan, consisting of two 5 mg dispersible tablets (pediatric formulation). PK sampling over 216 hours was conducted, and PK parameters were derived using non-compartmental methods. For Macitentan, geometric means ratio of peak plasma concentrations (Cmax ), plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC0- t ), and plasma concentration-time curve from zero to infinity (AUC0-∞ ) were 1.140, 0.974, and 0.974, respectively. The corresponding 90% confidence intervals fell entirely within the referenced range of 0.8000 to 1.2500, which is used for evaluation of bioequivalence. These results indicate no significant differences between the pediatric dispersible tablet and the adult film-coated tablet. Both formulations were well tolerated. The pediatric dispersible tablet is biocomparable to the adult film-coated tablet formulation.
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Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects.
Journal of clinical pharmacology, 2017Co-Authors: Milena Issac, Jasper Dingemanse, Patricia N SidhartaAbstract:Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (Ctrough ) of Macitentan and its active metabolite, ACT-132577, were obtained at steady state in 242 patients, indicating that mean Ctrough of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of Macitentan and its active metabolite, ACT-132577, a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN. A cross-study comparison showed that although Ctrough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for Macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (Cmax ) or area under the plasma concentration-time curve over a dosing interval (AUCτ ). Geometric mean ratios for Cmax and AUCτ were 1.08 and 1.22, respectively, for Macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to Macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.
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Pharmacokinetic and pharmacodynamic evaluation of Macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension
Expert opinion on drug metabolism & toxicology, 2015Co-Authors: Patricia N Sidharta, Stephan Krähenbühl, Jasper DingemanseAbstract:Introduction: Pulmonary arterial hypertension (PAH) is a chronic disorder of the pulmonary vasculature characterized by elevated mean pulmonary arterial pressure eventually leading to right-sided heart failure and premature death. Macitentan is an oral, once-daily, dual endothelin (ET)A and ETB receptor antagonist with high affinity and sustained receptor binding that was approved in the USA, Europe, Canada, and Switzerland for the treatment of PAH.Areas covered: This review discusses the pharmacokinetics (PK) and pharmacodynamics (PD) of Macitentan and its drug interaction potential based on preclinical and clinical data.Expert opinion: Up to date, Macitentan is the only registered treatment for PAH that significantly reduced morbidity and mortality as a combined endpoint in a long-term event-driven study. The safety profile of Macitentan is favorable with respect to hepatic safety and edema/fluid retention and may be better than that of other ET receptor antagonists such as bosentan and ambrisentan. The...
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Investigation of mutual pharmacokinetic interactions between Macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects
British journal of clinical pharmacology, 2014Co-Authors: Patricia N Sidharta, Paul L M Van Giersbergen, Michael Wolzt, Jasper DingemanseAbstract:Aim To study the mutual pharmacokinetic interactions between Macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects. Methods In this open-label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg Macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration−time profiles of Macitentan and its active metabolite ACT-132577 (treatments A and C) and sildenafil and its N-desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non-compartmentally. Results The pharmacokinetics of Macitentan were not affected by sildenafil. In the presence of sildenafil Cmax and AUCτ of the metabolite ACT-132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of Macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased Cmax and AUCτ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N-desmethylsildenafil were not affected by Macitentan. All treatments were well tolerated. Conclusion A minor, not clinically relevant, pharmacokinetic interaction was observed between Macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with Macitentan and sildenafil.
Richard N. Channick - One of the best experts on this subject based on the ideXlab platform.
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SAFETY AND EFFICACY OF Macitentan IN ELDERLY PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH): INSIGHTS FROM SERAPHIN
Journal of the American College of Cardiology, 2020Co-Authors: David Langleben, Pavel Jansa, Tomás Pulido, Richard N. Channick, Marion Delcroix, Sanjay Mehta, Nazzareno Galiè, Ardeschir Ghofrani, Rogério Souza, Gérald SimonneauAbstract:In SERAPHIN, the endothelin receptor antagonist Macitentan reduced morbidity/mortality risk by 45% in PAH patients. Here we explore the efficacy and safety of Macitentan in elderly PAH patients in SERAPHIN. SERAPHIN was a multicenter, double-blind, randomized, placebo-controlled, event-driven,
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Macitentan in pulmonary hypertension ph data from opus and orpheus real world data sets
European Respiratory Journal, 2019Co-Authors: Nick H Kim, Adele Morganti, Richard N. Channick, K Chin, Monika Brand, Lana Melendresgroves, Ashwin Ravichandran, Megan Flynn, Sandrine Leroy, Vallerie V MclaughlinAbstract:Introduction: The OPsumit® USers (OPUS) Registry captures real-world data on the use and safety profile of Macitentan. The OPsumit® Historical USers cohort (OrPHeUS) study was conducted to supplement the OPUS data with additional new Macitentan users. Aims and Objectives: To describe patient characteristics, treatment patterns, hepatic safety and survival in PH patients newly treated with Macitentan in OPUS/OrPHeUS. Methods: OPUS is an ongoing, prospective, multicentre, long-term, observational drug registry (NCT02126943). OrPHeUS was a retrospective, multicentre medical chart review (NCT03197688). Here we describe patients with follow-up data in OPUS/OrPHeUS. Results: By Oct 2018, the combined OPUS/OrPHeUS population consisted of 5070 patients, of which 4979 had follow-up data. At Macitentan initiation, median (Q1, Q3) age was 62 (51, 71) years and 2926 (58.8%) were on background pulmonary arterial hypertension therapy. WHO functional class (FC) was assessed in 2085 (41.9%) patients; 37.4% of those were in FC I/II and 62.6% in FC III/IV. Median (Q1, Q3) exposure to Macitentan was 13.2 (4.6, 26.1) months. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3x upper limit of normal (ULN) were experienced by 162 (3.3%) patients (incidence rate (IR): 0.025 [95% CI, 0.021, 0.029] per 1 person-year); ALT/AST ≥x3 ULN and bilirubin ≥2x ULN was experienced by 39 (0.8%) patients (IR: 0.006 [95% CI, 0.004, 0.008] per 1 person-year). The 12-month Kaplan-Meier survival estimate was 92% (95% CI, 91, 93). Conclusions: This is the largest data set of PH patients newly treated with Macitentan and confirms the hepatic safety profile of Macitentan with no unexpected safety findings.
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patient characteristics and treatment patterns with Macitentan in pulmonary arterial hypertension insights from the opus registry
Journal of Heart and Lung Transplantation, 2019Co-Authors: Richard N. Channick, Adele Morganti, K Chin, Nick H Kim, Monika Brand, Mona Selej, Vallerie V MclaughlinAbstract: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.
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Treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Real-World Experience with Macitentan
The Journal of Heart and Lung Transplantation, 2019Co-Authors: Richard N. Channick, Adele Morganti, K Chin, Monika Brand, Mona Selej, Vallerie V Mclaughlin, John W. Mcconnell, David Poch, Nick H KimAbstract: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.
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Macitentan in chronic thromboembolic pulmonary hypertension (CTEPH): experience from the OPUS registry
Pulmonary hypertension, 2018Co-Authors: Nick H Kim, Richard N. Channick, Monika Brand, Mona Selej, Vallerie V Mclaughlin, John W. Mcconnell, David Poch, Erwan Muros-le Rouzic, K ChinAbstract:Introduction: The OPsumit® USers Registry (OPUS; NCT02126943) provides real-world experience with Macitentan in patients with pulmonary hypertension, including CTEPH. Aims and objectives: To describe characteristics and safety in CTEPH patients enrolled in OPUS. Methods: OPUS is an ongoing, long-term, prospective, US, multicentre, observational drug registry of patients newly treated with Macitentan. This subgroup analysis describes CTEPH patients in OPUS. Adverse events (AEs) are descriptively compared with the overall PAH follow-up set. Results: As of October 2017, OPUS included 40 CTEPH patients with follow-up data. At Macitentan initiation, median age (range) was 66.5 (18–87) years; 67.5% were female. Median time (Q1, Q3) from CTEPH diagnosis was 15.1 (7.1, 42.8) months (n=36); 27 (68%) were receiving combination therapy. Median (Q1, Q3) exposure to Macitentan was 5.6 (3.3, 18.0) months. AEs that occurred in >5% of patients are shown in the table. One patient died. Conclusions: OPUS provides insight into real-world use of Macitentan for CTEPH. There were no unexpected safety findings in these patients.
M. C. Post - One of the best experts on this subject based on the ideXlab platform.
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Long-term real world clinical outcomes of Macitentan therapy in chronic thromboembolic pulmonary hypertension.
Respiratory medicine, 2020Co-Authors: M. C. J. Van Thor, R. J. Snijder, J. J. Mager, L. Ten Klooster, M. C. PostAbstract:Abstract Background Macitentan treatment for chronic thromboembolic pulmonary hypertension (CTEPH) in the routine clinical setting is increasing. However, ‘real world’ Macitentan experience is scarce and is needed to differentiate from controlled clinical trial settings. Objective We describe our outcomes and clinical ‘real world’ experience of Macitentan mono- and combination therapy with riociguat or sildenafil in CTEPH. Methods We included all consecutive CTEPH patients, either non-operated or with residual PH after pulmonary endarterectomy (PEA), treated with Macitentan in the St. Antonius hospital in Nieuwegein, the Netherlands, between 01-2014 and 11-2019. We describe clinical outcomes and adverse events (AEs) until 2 years after Macitentan initiation. Results In total 73 CTEPH patients on Macitentan were included, of which 18 patients were clinically inoperable (n = 7 declined PEA, n = 11 nonacceptable risk-benefit) and 55 had technically inoperable CTEPH (n = 48)/residual PH (n = 7). Clinically inoperable patients (mean age 72.4 ± 10.2 years, 61% female, 28% Macitentan monotherapy, observation period 2.0 (1.9–2.0) years) had a survival of 100% and clinical worsening (CW)-free survival of 88% at 2-year follow-up respectively, with a significant increased 6-min walking distance (6MWD). Technically inoperable/residual PH patients (mean age 62.1 ± 14.1 years, 60% female, 27% Macitentan monotherapy, observation period 2.0 (1.0–2.0) years) had a 2-year survival and CW-free survival of 86% and 68% respectively, with significant improved 6MWD and NT-proBNP. Nonsevere AEs were reported in 30% of all patients. Conclusion Macitentan mono- and combination therapy in non-operated CTEPH and residual PH is safe and improves clinical outcomes till 2-year follow-up.
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Safety of Macitentan in sarcoidosis-associated pulmonary hypertension: a case-series.
Sarcoidosis vasculitis and diffuse lung diseases : official journal of WASOG, 2020Co-Authors: H Mathijssen, J. J. Mager, M. P. Huitema, A.l.m. Bakker, R J Snijder, Jan C. Grutters, M. C. PostAbstract:Background Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and is associated with higher morbidity and mortality. Currently, there are no approved PH-targeted therapies for sarcoidosis-associated pulmonary hypertension (SAPH). Macitentan is frequently used as treatment for pulmonary arterial hypertension, but no results are known in the SAPH population. Objective We investigated the safety and effect of Macitentan as treatment for SAPH. Methods We retrospectively reviewed our patient database for all SAPH patients receiving Macitentan as treatment, with a minimum follow-up of twelve months for monitoring safety. Safety outcomes included reported side-effects, hospitalisations and mortality. Furthermore, six-minutes walking distance, New York Heart Association functional class and NT-proBNP levels were collected. Results Six cases (three men) with a median age of 64 years (range 52-74 years) were identified. During Macitentan treatment, one patient experienced side effects and aborted therapy after five days of treatment and died 16 months later. Three patients were hospitalised during treatment for congestive heart failure. Four patients showed improvement of their functional class and three patients in exercise capacity after 12 months of therapy. Conclusion Macitentan was well tolerated in five out of six cases with severe pulmonary sarcoidosis and PH. Functional capacity improved in four cases. Prospective controlled trials are warranted before therapeutic recommendations can be made. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 74-78).
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Bosentan or Macitentan Therapy in Chronic Thromboembolic Pulmonary Hypertension?
Lung, 2019Co-Authors: M. C. J. Van Thor, L. Ten Klooster, R. J. Snijder, J. C. Kelder, J. J. Mager, M. C. PostAbstract:Objective Research comparing bosentan and Macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although Macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH. Methods All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or Macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation. Results In total, 112 patients receiving bosentan or Macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for Macitentan. Two-year survival rate was 91% for bosentan and 80% for Macitentan (HR mortality Macitentan 1.85 [0.56–6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW Macitentan 2.16 [0.962–4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up. Conclusion CTEPH patients receiving bosentan or Macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.
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Bosentan or Macitentan Therapy in Chronic Thromboembolic Pulmonary Hypertension
Lung, 2019Co-Authors: M. C. J. Van Thor, R. J. Snijder, J. C. Kelder, J. J. Mager, L. Ten Klooster, M. C. PostAbstract:Research comparing bosentan and Macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although Macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH. All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or Macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation. In total, 112 patients receiving bosentan or Macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for Macitentan. Two-year survival rate was 91% for bosentan and 80% for Macitentan (HR mortality Macitentan 1.85 [0.56–6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW Macitentan 2.16 [0.962–4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up. CTEPH patients receiving bosentan or Macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.
Gérald Simonneau - One of the best experts on this subject based on the ideXlab platform.
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SAFETY AND EFFICACY OF Macitentan IN ELDERLY PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH): INSIGHTS FROM SERAPHIN
Journal of the American College of Cardiology, 2020Co-Authors: David Langleben, Pavel Jansa, Tomás Pulido, Richard N. Channick, Marion Delcroix, Sanjay Mehta, Nazzareno Galiè, Ardeschir Ghofrani, Rogério Souza, Gérald SimonneauAbstract:In SERAPHIN, the endothelin receptor antagonist Macitentan reduced morbidity/mortality risk by 45% in PAH patients. Here we explore the efficacy and safety of Macitentan in elderly PAH patients in SERAPHIN. SERAPHIN was a multicenter, double-blind, randomized, placebo-controlled, event-driven,
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Macitentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH): results from the randomised controlled MERIT study
Pulmonary Circulation and Pulmonary Vascular Disease, 2017Co-Authors: Gérald Simonneau, Nick H Kim, Zhi C. Jing, Andrea Maria D'armini, Peter F. Fedullo, Luke Howard, Xavier Jaïs, David P. Jenkins, Michael M. Madani, Nicholas MartinAbstract:The efficacy and safety of the endothelin receptor antagonist Macitentan in primary inoperable CTEPH, assessed by an independent adjudication committee, was evaluated in the randomised, double-blind MERIT study (NCT02021292). Patients in WHO functional class (FC) II–IV with pulmonary vascular resistance (PVR) ≥400 dyn∙sec/cm 5 and 6-minute walk distance (6MWD) of 150–450m were eligible. Treatment with phosphodiesterase type-5 inhibitors (PDE-5i) or oral/inhaled prostanoids was allowed for patients in WHO FC III–IV. Patients were randomised to placebo (n=40) or Macitentan 10 mg (n=40) once daily for 24 weeks; 61% were receiving a PDE-5i or oral/inhaled prostanoids at baseline; 96% PDE-5i. Compared with placebo, the PVR (primary endpoint) and 6MWD significantly improved in the Macitentan group. Macitentan-treated patients were less likely to experience WHO FC worsening vs placebo (Figure). PH-related disease progression occurred in 5.0% (Macitentan) and 17.5% (placebo) of patients. Most common adverse events (Macitentan vs placebo) were peripheral oedema (22.5% vs 10.0%) and decreased haemoglobin/anaemia (17.5% vs 2.5%). Five patients (placebo) prematurely discontinued treatment. Two patients (placebo) died. In the MERIT study, Macitentan led to significant improvements in cardiopulmonary haemodynamics and clinical parameters in inoperable CTEPH patients and was well tolerated.
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The potential for Macitentan, a new dual endothelin receptor antagonist, in the treatment of pulmonary arterial hypertension
Therapeutic advances in respiratory disease, 2014Co-Authors: Alexandru Steriade, Olivier Sitbon, Gérald Simonneau, Xavier Jaïs, Andrei Seferian, Laurent Savale, Etienne-marie Jutant, Florence Parent, Marc Humbert, David MontaniAbstract:In recent years in the management of pulmonary arterial hypertension (PAH), endothelin receptor antagonists (ERAs) represent a well-established class of therapeutic agents with clear beneficial effects. Macitentan (Opsumit ® ), a dual ERA optimized for efficacy and safety, is the newest drug in the class. Macitentan presents a number of key beneficial characteristics, including increased in vivo preclinical efficacy versus existing ERAs, resulting from sustained receptor binding and physicochemical properties that allow enhanced tissue penetration. The clinical pharmacokinetics studies also indicated a low predilection of Macitentan for drug-drug interactions. In the SERAPHIN trial, a phase III long-term study of PAH, Macitentan significantly reduced morbidity and mortality by 45% versus placebo, providing sustained long-term improvements in exercise capacity. No association was found between changes in exercise capacity and long-term clinical outcomes, but improved cardiopulmonary hemodynamics were recorded in Macitentan-treated patients irrespective of baseline background PAH therapy or World Health Organization functional class. Based on these favorable data, the US Food and Drug Administration approved the 10 mg/day dose in late 2013 and the same process has recently been concluded by the European Medicines Agency.
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S47 Effect of Macitentan on haemodynamics in patients with pulmonary arterial hypertension: results from the long-term, randomised, placebo-controlled SERAPHIN trial
Thorax, 2013Co-Authors: Gerry Coghlan, Loïc Perchenet, A Torbicki, Nazzareno Galiè, Lj Rubin, Gérald SimonneauAbstract:Introduction and objectives Macitentan, a novel dual endothelin receptor antagonist (ERA), significantly reduced morbidity and mortality in pulmonary arterial hypertension (PAH) patients in the SERAPHIN trial (NCT00660179), the first event-driven outcomes trial in PAH. A substudy in SERAPHIN investigated the effect of Macitentan on patients9 cardiac haemodynamics. Methods 742 PAH patients were randomised to placebo, Macitentan 3 mg, or Macitentan 10 mg once-daily. Stable background PAH therapy, except injectable prostanoids and other ERAs, were allowed. At selected centres, patients underwent right heart catheterisation at randomisation and Month 6. Changes from baseline to Month 6 for mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI) and mixed venous oxygen saturation (SvO2) were calculated for all patients and stratified in an exploratory analysis for background PAH therapy and baseline WHO functional class I/II vs III/IV. Median treatment effects (95% CL) between placebo and Macitentan are reported. Results 187 patients participated in the substudy (51% were treatment-naive and 56% in WHO FC III/IV). Baseline median values for all patients on placebo (n = 68), Macitentan 3 mg (n = 62) and 10 mg (n = 57) were: mRAP 7.0, 8.0, 7.0 mmHg; mPAP 52.0, 54.0, 52.3 mmHg; PVR 800, 785, 789 dyn·sec/cm5; CI 2.49, 2.23, 2.47 L/min/m2; and SvO2 66.0, 64.5, 66.5%, respectively. Overall, haemodynamic parameters improved at Month 6 with Macitentan and worsened with placebo. Beneficial treatment effects with Macitentan were statistically significant (P Conclusions Macitentan significantly improved cardio-pulmonary haemodynamics in PAH patients. Improvements in PVR and CI were consistent irrespective of background PAH therapy and baseline WHO FC.
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P149 Effect of Macitentan on pulmonary arterial hypertension-related hospitalisations: results from the randomised controlled SERAPHIN trial
Thorax, 2013Co-Authors: Gerry Coghlan, Loïc Perchenet, Richard N. Channick, Nazzareno Galiè, Lj Rubin, Gérald SimonneauAbstract:Introduction and objectives Macitentan, a novel dual endothelin receptor antagonist with sustained receptor binding, significantly reduced the risk of morbidity and mortality in pulmonary arterial hypertension (PAH) patients in the SERAPHIN trial (NCT00660179), the first event-driven outcomes trial in PAH. The effect of Macitentan on the risk of PAH-related hospitalisation was evaluated in this study. Methods In SERAPHIN, a multicentre, double-blind, placebo-controlled trial in PAH, patients (aged =12 years) in WHO functional class II–IV were randomised (1:1:1) to oral Macitentan 3mg, 10mg, or placebo once-daily. Time to death due to PAH or hospitalisation for PAH up to end of treatment (EOT), and time to hospitalisation for PAH up to EOT were evaluated (Kaplan–Meier analysis). Treatments were compared using log-rank tests. Annual rates of PAH-related hospitalisations and inpatient hospital days up to EOT were also assessed. Results For the 742 patients randomised, the median treatment duration was >2 years. The risk of death due to PAH or hospitalisation for PAH was reduced vs placebo by 33% (97.5% CL: 3–54%; P = 0.0146) in the Macitentan 3mg group and 50% (97.5% CL: 25–67%; P Conclusions Macitentan significantly reduced the risk of hospitalisation for PAH and the number of PAH-related hospitalisations and inpatient days (10mg only). These data offer further evidence that Macitentan has beneficial effects on long-term outcomes in PAH.
