act-132577 and macitentan

The endothelin peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular smooth muscle cells, the endothelin-B (ETB)-receptor is also found in endothelial cells, fibroblasts, and neuronal cells. Activation of the endothelin system plays a driving role in several chronic cardiovascular diseases and several endothelin receptor antagonists (ERAs) (bosentan (6), ambrisentan (83) and macitentan (43)) have successfully been introduced as oral treatments for the life threatening condition of pulmonary arterial hypertension (PAH). This digest highlights the medicinal chemistry of the pyrimidine based ERAs 6 and 43 and describes the story that started with bosentan and culminated in macitentan (43). A condensed overview of the competitive landscape in the field of ERAs puts the different strategies and tactics applied by the medicinal chemists involved in this endeavor into perspective.

Topics: Bosentan; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrimidines; Receptors, Endothelin; Structure-Activity Relationship; Sulfonamides

Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN.. The 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.. Sex, 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.. Modeling 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.. The 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).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Models, Biological; Pyrimidines; Sulfonamides; Treatment Outcome; Young Adult

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 (C

Topics: Adult; Aged; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Healthy Volunteers; Humans; Male; Middle Aged; Pyrimidines; Sulfonamides; Young Adult

Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Bosentan; Cell Line; Cricetinae; Dogs; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Hepatocytes; Humans; Liver; Male; Organic Anion Transporters; Organic Anion Transporters, Sodium-Dependent; Pyrimidines; Rats; Sulfonamides; Symporters

Macitentan is a potent, orally active, non-peptide antagonist of endothelin receptors with tissue-targeting properties, currently undergoing clinical development for the treatment of pulmonary arterial hypertension. The formation of its active metabolite, ACT-132577, as well as overall elimination of the drug, is catalyzed by the cytochrome P450 (CYP) system, predominantly CYP3A4 and to a lesser extent CYP2C19 isoenzyme. Macitentan is not a substrate of P-glycoprotein. Hepatic uptake is mostly driven by passive diffusion and is not dependent on organic anion-transporting polypeptide transport. This study aimed to investigate the magnitude of a possible effect of a potent CYP3A4 inhibitor, ketoconazole, on the pharmacokinetics of macitentan.. In a two-period, randomized, open-label, crossover study, 10 healthy subjects received each of the following treatments: Treatment A in which a single oral dose of 10 mg macitentan was administered on day 1 and Treatment B which consisted of initial daily treatment with ketoconazole 400 mg for 4 days, coadministration of macitentan and ketoconazole on the fifth day and continued administration of ketoconazole for 19 additional days.. In the presence of ketoconazole, the exposure to macitentan expressed as area under the plasma concentration-time curve was increased by approximately a factor of 2 and to ACT-132577 was reduced by approximately 26 %. Macitentan was well-tolerated with or without ketoconazole in this study and no relevant differences in safety parameters between the treatments were observed.. Although macitentan metabolism is indeed affected by CYP3A4 inhibition, the changes are not considered to be clinically significant and macitentan can be administered concomitantly with CYP3A4 inhibitors without need for dose adjustment.

Topics: Adult; Antifungal Agents; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Humans; Ketoconazole; Male; Pyrimidines; Sulfonamides; Young Adult

Macitentan is a novel dual endothelin receptor antagonist with sustained receptor binding in clinical development for pulmonary arterial hypertension. The present study compared the pharmacokinetics and safety of macitentan in healthy Caucasian and Japanese subjects and explored the potential sex differences.. In this single-center, open-label, phase I study 10 healthy subjects of each ethnic origin with a male/female ratio of 1:1 in each group were administered a single oral 10-mg dose of macitentan. Blood samples were taken to determine plasma levels of macitentan and its pharmacologically active metabolite, ACT-132577, and safety and tolerability were monitored using standard assessments.. For both macitentan and its metabolite, values for Cmax were similar but a shorter half-life was determined in Japanese subjects resulting in an exposure to both compounds being approximately 15% lower in Japanese when compared to Caucasian subjects. The exposure to macitentan was similar in Japanese males and females whereas Caucasian females had an approximately 25% higher exposure than Caucasian males. In both ethnic groups, females had an approximately 15% higher exposure to ACT-132577 than male subjects. Macitentan was well tolerated in both ethnic groups. There were no clinically significant differences in adverse event profile, clinical laboratory, electrocardiographic parameters, and vital signs between both groups.. The data suggest that the minor differences in pharmacokinetics between the two groups are not clinically relevant and no dose adjustment of macitentan based on Japanese ethnic origin or sex is necessary.

Topics: Adult; Asian People; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Female; Humans; Male; Pyrimidines; Sex Characteristics; Sulfonamides; White People; Young Adult

Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent.

Topics: Adult; Animals; Area Under Curve; CHO Cells; Cricetinae; Cricetulus; Cross-Over Studies; Cyclosporine; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Humans; Male; Organic Anion Transporters; Pyrimidines; Rifampin; Sulfonamides; Young Adult

Macitentan is a tissue-targeting, dual endothelin receptor antagonist, currently under phase 3 investigation in pulmonary arterial hypertension. In this study the disposition and metabolism of macitentan were investigated following administration of a single oral 10 mg dose of (14)C-macitentan to six healthy male subjects. The total radioactivity in matrices was determined using liquid scintillation counting. The proposed structure of metabolites was based on mass spectrometry characteristics and, when available, confirmed by comparison with reference compounds. Mean (± SD) cumulative recovery of radioactivity from faeces and urine was 73.6% (± 6.2%) of the administered radioactive dose, with 49.7% (± 3.9%) cumulative recovery from urine, and 23.9% (± 4.8%) from faeces. In plasma, in addition to parent macitentan, ACT-132577, a pharmacologically active metabolite elicited by oxidative depropylation and the carboxylic acid metabolite ACT-373898 were identified. In urine, four entities were identified, with the hydrolysis product of ACT-373898 as the most abundant one. In faeces, five entities were identified, with the hydrolysis product of macitentan and ACT-132577 as the most abundant one. Concentrations of total radioactivity in whole blood were lower compared to plasma, which indicates that macitentan and its metabolites poorly bind to or penetrate into erythrocytes.

Topics: Carbon Radioisotopes; Chromatography, Liquid; Endothelin Receptor Antagonists; Feces; Humans; Male; Metabolic Networks and Pathways; Middle Aged; Molecular Structure; Pyrimidines; Scintillation Counting; Sulfonamides; Tandem Mass Spectrometry

Macitentan and its active metabolite, aprocitentan, are non-peptide, potent, dual endothelin receptor antagonists. Macitentan is approved for the treatment of pulmonary arterial hypertension in adults, at a dose of 10 mg/day.. The objective of this study was to develop a comprehensive population model to describe the pharmacokinetics of macitentan and aprocitentan in healthy adults and adult subjects with pulmonary arterial hypertension.. Pharmacokinetic data of 452 subjects in nine studies, after single and repeated doses (dose range 0.2-600 mg), were pooled for a non-linear mixed-effects analysis and the assessment of covariates, i.e., body weight, age, sex, race, renal and hepatic impairment, health status (healthy volunteers vs patients with pulmonary arterial hypertension), and formulation (capsules vs tablets) on pharmacokinetic parameters.. The final model was an open one-compartment disposition model, with linear elimination for macitentan and linear formation and elimination for aprocitentan. A semi-mechanistic absorption model described the dose dependency and multiple peaks observed for macitentan. For a female patient with pulmonary arterial hypertension after oral administration at 10 mg, macitentan reached a maximum concentration after 9 h and, following daily dosing, reached steady state after 3 days with a twofold accumulation factor. The apparent volume of distribution was 34 L and clearance was 1.39 L/h. Aprocitentan reached maximum concentration after 51 h and steady state after 9 days, with a 12.5-fold accumulation factor. Body weight, sex, race, renal impairment, health status, and formulation were statistically significant covariates on pharmacokinetic parameters.. The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations. Several covariates significantly influenced the pharmacokinetics of macitentan and aprocitentan, but none was considered clinically relevant.

Topics: Adult; Female; Healthy Volunteers; Humans; Pulmonary Arterial Hypertension; Pyrimidines; Sulfonamides

Treatment of pulmonary arterial hypertension (PAH) by vasodilator drug monotherapy is often limited in its effectiveness. Combination therapy may help to improve treatment and to reduce drug toxicity. This study assessed the combination of the endothelin receptor antagonist macitentan and the phosphodiesterase-5 inhibitor vardenafil in a human ex vivo model.. Study patients did not suffer from PAH. Human pulmonary arteries (PA) and veins (PV) were harvested from resected pulmonary lobes. Contractile forces of blood vessel segments in the presence and absence of the vasodilator drugs macitentan, its main metabolite ACT-132577, and vardenafil were determined isometrically in an organ bath.. Macitentan 1E-7 M was sufficient to significantly abate endothelin-1-induced vasoconstriction in PA. A concentration of 1E-6 M was required for significant effects of macitentan on PV and of ACT-132577 on both vessel types. Combination of 1E-7 M macitentan and 1E-6 M vardenafil inhibited sequential constriction with endothelin-1 and norepinephrine of PA significantly more than either compound alone. Effects of 3E-7 M and 1E-6 M macitentan and effects of all doses of ACT-132577 were not further enhanced by 1E-6 M vardenafil.. These data suggest that vasodilator effects of macitentan and vardenafil combined may surpass monotherapy in vivo if drug doses are adjusted properly. Vasodilation by the longer-acting metabolite ACT-132577 was not further enhanced by vardenafil.

Topics: Aged; Antihypertensive Agents; Arterial Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; In Vitro Techniques; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrimidines; Sulfonamides; Vardenafil Dihydrochloride; Vasodilation; Vasodilator Agents

Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577.. A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro.. The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH.. This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).

Topics: Adult; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Humans; Ketoconazole; Male; Models, Biological; Pyrimidines; Rifampin; Sildenafil Citrate; Sulfonamides; Warfarin

To investigate the effects of the endothelin 1 (ET-1) receptor antagonists (ETRA) macitentan, its active metabolite ACT-132577, and bosentan on myofibroblast activation and extracellular matrix production induced by ET-1 in cultured systemic sclerosis (SSc) and control skin fibroblasts.. Fibroblasts were obtained from skin biopsies of 6 patients with SSc and 5 healthy subjects. Some cultured cells were untreated or treated with macitentan, ACT-132577, or bosentan alone (10 μM). Other cultured cells were treated with ET-1 alone (100 nM) or with ETRA, and after 1 h, also with ET-1. After 48 h of treatment, myofibroblast activation was investigated to evaluate the α-smooth muscle actin (α-SMA) expression by immunofluorescence; type I collagen (COL-1) and fibronectin (FN) were investigated by immunocytochemistry, Western blotting, and quantitative real-time PCR (qRT-PCR). Statistical analysis was performed by the nonparametric Mann-Whitney U test.. In cultured SSc skin fibroblasts, only the treatment with macitentan significantly reduced the basal level of α-SMA expression (p = 0.03 vs untreated cells). Macitentan also significantly reduced the basal level of COL-1 synthesis, similarly to bosentan (p < 0.05 vs untreated cells). Macitentan or ACT-132577 antagonized the ability of ET-1 to further induce α-SMA expression (p = 0.03), COL-1, and FN synthesis (p = 0.03, p = 0.005); bosentan showed similar effects. These results obtained by immunofluorescence and immunocytochemistry were confirmed by Western blotting and qRT-PCR. The downregulatory effects exerted by ETRA were observed also in cultured human control skin fibroblasts.. Macitentan and ACT-132577 seem to downregulate in vitro the profibrotic myofibroblast phenotype induced by ET-1 in cultured human SSc skin fibroblasts.

Topics: Actins; Aged; Bosentan; Down-Regulation; Endothelin A Receptor Antagonists; Female; Fibroblasts; Humans; Male; Middle Aged; Pyrimidines; Scleroderma, Systemic; Skin; Sulfonamides

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET(A) with significant affinity for the ET(B) receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.

Topics: Administration, Oral; Animals; Antihypertensive Agents; CHO Cells; Cricetinae; Cricetulus; Drug Discovery; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Pyrimidines; Rats; Rats, Inbred Dahl; Sulfonamides