bay-63-2521 and macitentan

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.

Topics: Adult; Aged; Angioplasty, Balloon; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Epoprostenol; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Molecular Targeted Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Walk Test

Pulmonary hypertension (PH) is often caused by left heart disease (LHD) such as heart failure (HF) or valvular heart disease. Historically, few randomized controlled trials have evaluated the off-label use of medications for treating pulmonary arterial hypertension (PAH) in patients with PH-LHD. However, multiple randomized controlled trials have been published over the last decade that investigated their use in patients with PH-LHD. In addition, recent updates in the classification and definitions of PH have led to an improved recognition of PH-LHD phenotypes, notably combined post-capillary and pre-capillary PH and isolated post-capillary PH. In this systematic review, we show that PAH medications should not be recommended in two distinct HF populations: patients with HF without definitive PH diagnosis and patients with isolated post-capillary PH due to HF. In addition, the use of bosentan or macitentan is not recommended in patients with combined post-capillary and pre-capillary PH due to HF, but sildenafil may be considered to improve pulmonary hemodynamics and exercise capacity in patients with combined post-capillary and pre-capillary PH due to HF. Riociguat 2 mg 3 times daily may also be considered to improve pulmonary hemodynamics in patients with combined post-capillary and pre-capillary PH due to heart failure with reduced ejection fraction but not heart failure with preserved ejection fraction. The postoperative use of sildenafil in the setting of PH after valvular heart disease intervention was evaluated. Limited clinical data and safety concern warrants caution with the postoperative use of sildenafil in patients with PH due to valvular heart disease. Despite recent advances in the understanding of PAH medications for patients with PH-LHD, uncertainty remains about their utility in distinct subgroups. Nonetheless, PAH pharmacotherapy should generally be avoided for most patients with PH-LHD.

Topics: Bosentan; Endothelin Receptor Antagonists; Heart Diseases; Hemodynamics; Humans; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides

Pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis if not treated. Pharmacological treatment options for PAH have increased significantly over the past 10 years, with availability of intravenous, oral and inhaled drugs targeting the nitric oxide, endothelin and prostacyclin pathways. Treatment with these therapies in specialised pulmonary hypertension centres has resulted in reductions in patient symptoms, disease progression and mortality, and improved exercise capacity. Recognition of chronic thromboembolic pulmonary hypertension is important, as this cause of pulmonary hypertension may be amenable to surgical treatment. Several new oral drugs, including macitentan, riociguat and selexipag, some of which have novel modes of action, and the use of combinations of PAH drugs have recently been shown to be beneficial in treating PAH and are likely to change treatment for this condition in the future.

Topics: Acetamides; Antihypertensive Agents; Australia; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Pyrazines; Pyrazoles; Pyrimidines; Sulfonamides; World Health Organization

The development of therapeutic concepts in pulmonary hypertension (PH) is intimately linked with the unraveling of pathogenetic sequelae. This perspective highlights advances in our understanding of the regulation of vasomotion and vascular remodeling that have led to "reverse-remodeling" and regenerative strategies as novel treatment concepts. Progress has been made in understanding redox-dependent signaling; inflammatory sequelae; and transcription factor, ion channel, and metabolic abnormalities, as well as growth factor-dependent hyperproliferation that underlies PH. We are, however, far from understanding the molecular pathways that differentially drive the various vascular phenotypes (intimal thickening, media hypertrophy, adventitial thickening, plexiform lesions, vascular pruning) in this disease. Antiproliferative strategies, transcription factor-based therapies, inflammation/immune cell-focused approaches, and epigenetic modulation-based therapies are all novel treatment concepts for PH. The proangiogenic potential of genetically engineered mesenchymal stem cells and endothelial progenitor cells has been explored as a regenerative strategy. The progress that has been made in identifying important cellular and molecular mechanisms and applying this knowledge to novel therapies is largely restricted to group 1 PH. However, understanding the molecular sequelae underlying PH in groups 2 through 5 PH is also urgently needed.

Topics: Angiogenesis Inhibitors; Antihypertensive Agents; Epigenesis, Genetic; Familial Primary Pulmonary Hypertension; Histone Deacetylase Inhibitors; Humans; Hypertension, Pulmonary; Protein Kinase Inhibitors; Pulmonary Artery; Pyrazoles; Pyrimidines; Sulfonamides; Vasodilation; Vasodilator Agents

Available targeted therapies for pulmonary arterial hypertension are capable only of slowing progression of the disease and a cure remains elusive. However with the improved understanding of the pulmonary vascular remodeling that characterizes the disease, there is optimism that the disconnect between preclinical and clinical studies may be bridged with some of the newer therapies that are now at different stages of clinical evaluation. This article examines the evidence behind these new candidate treatments that may become part of the arsenal available for clinicians managing this devastating disease.

Topics: Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Receptors, Epoprostenol; Sulfonamides

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

Topics: Acetamides; Animals; Antihypertensive Agents; Benzamides; Clinical Trials as Topic; Drugs, Investigational; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epoprostenol; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lisuride; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Serotonin Antagonists; Sulfonamides

Use of endothelin receptor antagonists (ERAs) and riociguat, approved for treatment of pulmonary hypertension (PH), is contraindicated during pregnancy due to reported teratogenicity in animals. We aimed to investigate prescribing of these drugs in girls/women of childbearing age and to explore - as a secondary aim - the occurrence of pregnancies exposed to these drugs. Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from 20% of the German population) we conducted cross-sectional analyses to determine prescribing prevalence of ERAs and riociguat between 2004 and 2019 and to characterize users and prescribing patterns. In a cohort analysis, we assessed the occurrence of pregnancies exposed to these drugs in the critical time window. Overall, we identified 407 women with ≥ 1 dispensation of bosentan between 2004 and 2019; the respective number was 73 for ambrisentan, 182 for macitentan, 31 for sitaxentan, and 63 for riociguat. In nearly all years, more than 50% of the girls/women were ≤ 40 years. Age-standardized prevalence was highest for bosentan (0.04/1000) in 2012 and 2013, followed by macitentan (0.03/1000) in 2018 and 2019. We observed 10 exposed pregnancies: 5 to bosentan, 3 to ambrisentan, and 2 to macitentan. The increased prevalence of macitentan and riociguat from 2014 onwards might reflect changes in PH treatment. Even though PH is a rare disease and pregnancy should be avoided in women with PH, particularly if they use ERAs, we identified pregnancies exposed to ERAs. Multi-database studies will be needed to assess the risk of these drugs on the unborn child.

Topics: Animals; Bosentan; Cross-Sectional Studies; Endothelin Receptor Antagonists; Female; Hypertension, Pulmonary

The article presents a clinical case of successful triple combination therapy in a female patient with functional class III idiopathic pulmonary arterial hypertension. Supplementing the previous macitentan and riociguat treatment with selexipag reduced the severity of clinical manifestations of pulmonary hypertension. Also, the treatment efficacy was demonstrated by improvement of laboratory and instrumental indexes. Time-related changes were evaluated at 3 months after initiation of the selexipag treatment.

Topics: Acetamides; Antihypertensive Agents; Familial Primary Pulmonary Hypertension; Female; Humans; Pyrazines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Bosentan; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Insurance Coverage; Japan; Phenylpropionates; Prevalence; Prognosis; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyridazines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Universal Health Insurance

Macitentan 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.. Two 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.. Healthy 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 (C. Ninety 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 t. Macitentan 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.

Topics: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily G, Member 2; Drug Interactions; Healthy Volunteers; Humans; Male; Middle Aged; Neoplasm Proteins; Pyrazoles; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Young Adult

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.

Topics: Aged; Bosentan; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Survival Rate; Walk Test

In the past 18 months, the U.S. Food and Drug Administration approved macitentan, riociguat, and treprostinil as oral agents for the treatment of pulmonary arterial hypertension (PAH); riociguat also became the first agent approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). These new agents are welcome additional therapeutic options for PAH and CTEPH. However, their use can be complicated by potential drug interactions, adverse effects, dosing complexity, and cost. Macitentan, the newest endothelin receptor antagonist, showed significant benefits in a long-term event-driven trial of morbidity and mortality. Dosed once daily and with minimal liver toxicity, it has potential drug interactions with potent CYP 3A4 inhibitors and inducers, and can decrease hemoglobin levels. Riociguat is approved for PAH and clinically inoperable CTEPH to improve exercise capacity and functional status. Riociguat requires dose titration beginning with 1 mg up to 2.5 mg three times a day, as tolerated, and should be used with caution in patients with underlying risk factors for systemic hypotension. Oral treprostinil, approved to improve exercise capacity in PAH, is associated with gastrointestinal side effects and headaches that are often dose limiting. Doses can begin with 0.125 mg or 0.25 mg twice a day with gradual increases on up to a weekly basis, as tolerated. Thrice daily dosing and administration with a meal can improve tolerance. These newer agents represent advances, but their specific roles in relation to pre-existing therapies are undergoing further evaluation. Therefore, close collaboration with clinicians at centers with therapeutic expertise is highly recommended to optimize patient outcomes.

Topics: Administration, Oral; Antihypertensive Agents; Chronic Disease; Drug Approval; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Sulfonamides; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Algorithms; Animals; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Endothelin Receptor Antagonists; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Indoles; Pulmonary Artery; Pyrazoles; Pyridones; Pyrimidines; Rituximab; Scleroderma, Systemic; Sulfonamides

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Pulmonary Veno-Occlusive Disease; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Thromboembolism; Treatment Failure; Vasodilator Agents

Topics: Benzamides; Biomarkers; Biomedical Research; Clinical Trials as Topic; Endothelin A Receptor Antagonists; Exercise Test; Hospitalization; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Multicenter Studies as Topic; Piperazines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Sulfonamides; Walking

Topics: Anti-Anxiety Agents; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Approval; Maytansine; Piperazines; Pyrazoles; Pyrimidines; Sulfides; Sulfonamides; Vortioxetine

Topics: Cardiovascular Agents; Clinical Trials as Topic; Congresses as Topic; Diagnostic Techniques, Cardiovascular; Disease Management; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Respiratory Function Tests; Sulfonamides; Therapies, Investigational; Ventricular Dysfunction, Right

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Topics: Aminorex; Antihypertensive Agents; Appetite Depressants; Bosentan; Dasatinib; Epoprostenol; Familial Primary Pulmonary Hypertension; Fenfluramine; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Iloprost; Phenylpropionates; Piperazines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridazines; Pyrimidines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Thiazoles; Vasodilator Agents

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Benzamides; Drug Therapy, Combination; Early Medical Intervention; Epoprostenol; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Piperazines; Pyrazines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides