American Journal of Advanced Drug Delivery
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Review Article Pulmonary Arterial Hypertension: Role of Ambrisentan
Pranay Wal*1, Ankita Wal2, Shweta Tripathi2 and Dr. Awani K Rai2
1Jodhpur National University, Jodhpur, India. 2Assistant Professor, Pranveer Singh Institute of Technology, bhauti road, Kanpur (U.P) 208020. India.
Date of Receipt- 14/09/2013 ABSTRACT Date of Revision- 28/09/2013 Date of Acceptance- 29/09/2013 Increasing numbers of experimental investigations and recently also of clinical trials strongly suggest an integral involvement of the endothelin (ET) system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system.Ambrisentan (LU 208075)approved by the US Food and Drug Administration in 2007, a selective ETA-receptor antagonist, is an orally active diphenyl propionic acid derivative that was recently approved for treatment of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms.. It has been shown to have a very promising efficacy to safety ratio in the initial clinical trials. Phase II and Phase III trials with ambrisentan in pulmonary arterial hypertension have been performed. Pulmonary arterial hypertension (PAH) is a rare and progressive disease of the pulmonary arterial circulation that is characterized by a progressive rise in pulmonary vascular resistance, eventually leading to right-heart failure and death. Endothelin (ET) is a potent vasoconstrictor with mitogenic, hypertrophic and pro-inflammatory properties. Therefore, blockade of ET receptors has been suggested as an attractive target in a number Address for of acute and chronic cardiovascular indications, including pulmonary Correspondence arterial hypertension (PAH), systemic hypertension, and heart failure. Jodhpur National In Phase III clinical trials in patients with PAH, ambrisentan (2.5–10 University, Jodhpur, mg orally once-daily) improved exercise capacity, time to clinical India. worsening, WHO functional class, and quality of life compared with Phone number: +91- placebo. This review discusses the endothelin family of proteins and receptors and their role in the pathophysiology of pulmonary 9795967709 . hypertensive diseases. E-mail: Keywords: Pulmonary Hypertension, Endothelin, Endothelin [email protected] receptor antagonist, Ambrisentan.
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INTRODUCTION Pulmonary Arterial Hypertension (PAH) PAH differs from ordinary percent of patients), fatigue, dizziness, hypertension, which is high blood pressure syncope or fainting (present in 13 percent of throughout the body. In PAH, the high blood patients), weakness (present in 19 percent of pressure is in the arteries between the heart patients), peripheral edema, and chest pains and lungs. This causes the blood vessels that during physical activity. A key factor go from the heart to the lungs (or pulmonary underlying the increase in pulmonary arteries) to become tight, thick, and stiff. vascular resistance in PAH is thought to be Typically, the pulmonary arteries are open pulmonary endothelial dysfunction, and elastic, which creates no resistance to involving impaired production of blood flow.1 Pulmonary arterial vasodilators, such as nitric oxide (NO) and hypertension (PAH) is defined as a blood prostacyclin, and overexpression of pressure elevation in the vessels supplying vasconstrictors, such asendothelin-1.11 the lung. It is characterized by vasoconstriction and vascular obstruction The Venice 2003 Revised Classification that eventually lead to increased pulmonary system is12 : vascular resistance and right heart failure.2 WHO Group I - Pulmonary arterial As the disease progresses, patients hypertension experience a progressive rise in pulmonary WHO Group II - Pulmonary artery pressure and pulmonary vascular hypertension associated with left heart resistance which leads to heart failure and disease 3,4,5 premature death. These high pressures WHO Group III - Pulmonary make it difficult for the heart to pump blood hypertension associated with lung 6 through the lungs to be oxygenated. It was diseases and/orhypoxemia previously defined as mean pulmonary WHO Group IV - Pulmonary artery pressure (MPAP)>25 mmHg at rest or hypertension due to chronic thrombotic >30 mmHg with exercise, but the definition and/or embolicdisease was simplified to resting (MPAP) WHO Group V – Miscellaneous. ≥25mmHg based on a review of current 7 literature in 2008. At the same time, Over the last 13 years, 6 drugs pulmonary vascular tone may be increased comprising 3 different drug classes have and the ability of the pulmonary circulation been approved for the treatment of PAH in to dilate or recruit underutilized vessels in 8 the US (Table 1). response to increased flow is reduced. The five-group World Health These changes result in a progressive Organization (WHO) classification scheme increase in pulmonary vascular was last updated in 2008 at the 4th World resistance(PVR) that increases right Symposium on Pulmonary Hypertension ventricular afterload, reduces exercise (Table 2). Patients in WHO Group1 are tolerance and in most cases results in right 9 classified as having pulmonary arterial ventricular failure. hypertension (PAH), whereas patients in A key problem in treating PAH is 10 Groups 2 to 5 are classified as non-PAH or the difficulty in confirming the diagnosis. PH. Group 1 adds the criterion of pulmonary The early common symptoms include: arterial wedge pressure of ≤15 mmHg and breathlessness or dyspnea (present in 60 pulmonary vascular resistance (PVR) of ≥3
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Wood’s units. Group 1 also include increase in vasoconstrictor and proliferative sidiopathic and drug- and toxin-induced mediators and a decrease in vasodilator and PAH.13 The World Health Organization antiproliferative mediators.23 (WHO) classification of PAH is based on Among the currently targeted patients’ function, with class I signifying therapies licensed in the U.S. for use in PAH no limitation of usual daily physical activity, are: the ETRAs (ambrisentan and bosentan), class II indicating mild limitation of physical the PDE-5s (sildenafil and tadalafil), and the activity, class III representing marked prostaglandins (epoprostenol, iloprost, and limitation of physical activity, and class IV treprostinil). Clinical trials with these indicating inability to perform any physical targeted therapies have demonstrated activity at rest, with possible signs of right- improvements in exercise capacity, ventricular failure.14 hemodynamics, symptoms, and quality of 24 The diagnosis of PAH is based on life. right heart catheterization demonstrating a Data suggesting a role of the mean pulmonary artery pressure (PAP) endothelins in the pathophysiology of PAH greater than 25 mm Hg with a normal left include elevated circulating levels of atrial pressure, as estimated by a pulmonary endothelin-1 (ET-1) in patients with PAH capillary wedge pressure (PCWP) less than and increased expression of ET-1 in plexi 25 15 mm Hg, and pulmonary vascular form lesions. Occluding the distal resistance (PVR) greater than 3 Wood pulmonary arteries of PAH patients. ET is units.15 one of many important neurohormones that However, due to the rate of disease play arole in the pathophysiology of PAH. progression and the incurability of PAH, the ET-1 is a potent vasoconstrictor produced in goals of therapy still focus upon:1) the endothelium of pulmonary artery smooth preventing clinical worsening; and 2) muscle cells. ETA receptors on the improving exercise capacity, functional endothelial cells stimulate vasoconstriction class, hemodynamics, survival and quality and proliferation while the ETB receptors are of life. The understanding of the thought to stimulate the release of NO and pathogenesisof PAH has increased PGI2, leading to vasodilation and substantially over the last few years,16 as counteracting the effects of ETA and have treatment options, including ultimately ET-1. In PAH, lessET-1 is prostaglandins and Potential cleared. Higher levels of ET-1 correspond 26 phosphodiesterase inhibitors17,18 and ET with more severe disease and prognosis. receptor antagonists.19,20 There are several mechanisms through which ET receptor The Endothelins antagonists might improve PAH and/or right ventricular hypertrophy and failure. In In 1985, Hickey et al described an addition to direct reduction of pulmonary endothelium-derived contractile factor that artery tone through blocking ET receptors was subsequently isolated and sequenced by localized on vascular smooth muscle cells, a Yanagisawa et al from porcine aortic endothelial cell cultures in 1988 and named reduction of vascular media hypertrophy and 27 thus a positive effect on vascular remodeling endothelin. The endothelins are a family of has been described in different preclinical naturally occurring peptides that include experiments.21,22 Progression of PAH is endothelin1(ET-1), endothelin-2 (ET-2), and accompanied by impaired endothelial cell endothelin-3 (ET-3). They are encoded by functioning that is characterized by an three different genes located on chromosomes 6, 1 and 20, respectively.28 Endothelins are
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X mainly produced by vascular endothelial exhibit similar affinities for the ETs.36,37 cells, and to a lesser extent by vascular The intracellular mechanisms by smooth muscle cells, airway epithelial cells, which ETs induce smooth muscle macrophages, fibroblasts, cardiac myocytes, contraction have not been fully brain neurons, and pancreatic islet cells29 and elucidated.38These receptors are seven- secreted from the vascular endothelium in transmembrane G protein-coupled response to numerous stimuli, including membrane proteins. By associating with hypoxia, ischemia, shear stress, and growth different Gα proteins, both receptors can factors and other neurohormones activate different down stream protein (eg,angiotensin II,norepinephrine).30 All are kinases. ET-1 causes a transient increase in 21 amino acid peptides containing 2 disulfide the intracellular concentration of free Ca2+ bonds.They are produced in endothelial cells ions, followed by a sustained elevation of lining the blood vessels.ET-1 acts primarily as free Ca2+ ions for 30 to 60 minutes resulting a local autocrine and paracrine factor rather in prolonged contraction.39 The transient than as an endocrine hormone.31 ET-1 was increase represents Ca2+ ions released from ++ originally isolated from the supernatent of the intracellular pool of free Ca2 via cultured porcine aortic endothelial calls, and activation of phospholipase C (PLC).40 ET- is one of the most potent vasoconstrictor A and ET-B to activate phospholipases currently known.32 Human ET-1 is Derived resulting in elevation of inositol phosphate, from the a 212 amino acid precursor protein diacylglycerol, eicosanoids, calcium.41,42 (preproendothelin) which is cleaved by ET-2 display similar pharmacology to ET-1, neutral endopeptidase (a furin like peptidase) where as ET-3 is a weaker vasoconstrictor to form a 38 amino acid pro ET-1 or but more potent inhibitor of platelet bigendothelin. Big endothelin is essentially aggregation . devoid of biologically activity, Endothelin Activation of ET-A and ET-B converting enzyme-1 (ECE-1) converts big receptors on smooth muscle cells mediates endothelin to mature endothelin peptide (ET- the vasoconstrictive and mitogenic effects of 1). This conversion is physiologically ET. The mitogenic effects of ET-1 are important because ET-1 is a much more mediated by the activation of protein kinase potent vasoconstrictor than big-ET-1 (about C secondary to increases in 140-fold) as shown in Figure1.33 diacylglyceroland intracellular calcium, Various evidence suggests that ET-1 which in turn stimulate the production of might have a role in the pathogenesis and cytokines and growth factors.43 The ET-A progression of PAH. For example, elevated receptors are primarily expressed on levels of ET-1 have been found in patients vascular smooth Muscle cells and cardiac with PAH, and PAH was found to be myocytes and their activation mediates the associated with the increased expression of vasoconstrictive and motohenic effect of ET-1 in vascular endothelial cells of Endothelin-1 (ET-1) ; in contrast, ETB pulmonary arteries.34,35 ET-1 binds to 2 receptors are localized predominantly on heptahelical G-protein-coupled receptors, endothelial cells, and to alesser extent, on named endothelin receptor-A (ETA) and smooth muscle cells and on fibroblasts,44 endothelin receptor-B (ETB).The two where they stimulate vasodilation via subtypes of endothelin receptors have activation of endothelial cell Nitric oxide distinct ligand preference; ETA receptors synthesis and ET-1 clearence via Receptor are ET-1-selective, with an affinity order of mediated endocytosis, although some ETB ET-1≥ET-2 > ET-3, whereas ETB receptors receptor also located on smooth muscle
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X cells, where they mediates vasoconstriction in pulmonary arterial hypertension,58-60 A and cellular proliferation.45, 46 third ETRA – sitaxentan has been approved Endothelin receptor A has 10 times in the European Union, Australia, and more binding affinity for ET-1 and ET-2 Canada. These agents differ in their than for ET-3 while ETB has equally potent selectivity for the ETA and ETB receptors affinities to all 3 endogenous endothelins.47- and also with regard to their 49 Therefore, a selective ETA receptor pharmacokinetic properties. Endothelin antagonist may theoretically offer greater receptor antagonism is a well-established beneficial effects in PAH than antagonists of approach to blocking the ET-1 system in both ETA and ETB receptors.50, 51 PAH. Endothelin receptor antagonists Circulating plasma levels of ET-1 (ERAs) are either ETA selective, such as are raised in patients with PAH. sitaxsentan and ambrisentan, or nonselective Importantly, increased circulating levels of for the ETA and ETB receptors, such as ET-1 correlate with increased right atrial bosentan. ERAs block the activation of pressure, increased pulmonary vascular endothelin receptors on endothelial or resistance, decreased pulmonary artery smooth muscle cells, thereby inhibiting the oxygen saturation and increased mortality in vasoconstriction and cellular proliferation patients with PAH.52-55 Furthermore, there mediated by endothelin.61-67 is an increase in the expression of ET-A and Theoretically, selective ETA-receptor ET-B receptors in the lungs of patients with antagonists should be more effective in IPAH and PAH associated with congenital achieving vasodilation than non-selective heart disease, although the relative ETA/ETB receptor antagonists, given the proportion (60% ETA and 40% ETB) role played by ETB receptors in both remains constant.56 vasodilation and ET-1 clearance.68 Selective Endothelin (ET) is among the inhibition of ETA receptors may be strongest endogenous vasoconstrictors preferential to non-selective receptor known and a potent mitogen. A rich body of antagonism by permitting maintenance of experimental evidence suggests that ET vasodilator and clearance functions specific contributes to vascular remodeling and end- to ETB receptors on the endothelial cells, organ damage in several cardiovascular while preventing the vasoconstriction and conditions. Therefore, blockade of ET cellular proliferation mediated by ETA .It is receptors has been suggested as an attractive generally agreed that selective ETA target in a number of acute and chronic antagonists display a more than 100- fold cardiovascular indications, including selectivity for the ETA receptor subtype. pulmonary arterial hypertension (PAH), The selectivity, usually calculated from in systemic hypertension, and heart failure. vitro competitive receptor assays, can also Subsequently, a large number of be estimated in vivo on the basis of changes Phase II and III trials were conducted for a in circulating levels of ET-1. An increase in variety of disorders, including heart failure, circulating ET-1 levels following cancer, pulmonary arterial hypertension, administration of an ERA would reflect arterial hypertension, proteinuric renal functional blockade of the ETB receptor.69 disease, and autoimmune diseases.57 More recently, the ETA-selective, Despite such intensive efforts, ERAs have sulfonamide-class ERA sitaxsentan was been approved by the U.S. Food and Drug approved in the EU. Ambrisentan, a non- Administration for only two drugs and only sulfonamide, propanoic-acid class, ETA- two indications: bosentan and ambrisentan selective ERA, is in late-stage clinical
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X development. Bosentan (Tracleer®) was with the aim to simplify the structure and to approved in 2001 and has been moderately enhance the binding activity led to a series successful in improving quality of life for of potent orally available ETA-selective PAH sufferers, but is worrisome because of receptor antagonists.80 The active liver damage and interactions with other enantiomer of the first compound was medications (oral contraceptives, statins, named LU 135252, which was studied ketoconazole, amiodarone, glyburide, clinically as darusentan (Fig. 2). Slight etc.).70,71 modification of the structure of darusentan led to a similar compound, LU 208075, Ambrisentan therapy in pulmonary which was named ambrisentan. arterial hypertension Finally, ambrisentan is the latest endothelin antagonist to enter the market. Chemistry and Development of The orphan drug is indicated for the Ambrisentan treatment of pulmonary arterial hypertension and is available only through a limited Several different structural classes of distribution system.81 ERAs, ranging from peptidic and LETAIRIS is the brand name for peptidomimetic structures to small organic ambrisentan, an endothelin receptor molecules suitable for oral administration antagonist that is selective for the endothelin have been discovered within the last decade. type-A (ETA) receptor. The chemical name Bosentan, one of the first orally active of ambrisentan is (+)-(2S)-2-[(4,6- compounds with an antagonistic effect of dimethylpyrimidin-2-yl)oxy]-3-methoxy- ETA and ETB, is a tetra-substituted 72 3,3-diphenylpropanoic acid. It has a pyrimidine. It was the first ERA approved molecular formula of C22H22N2O4 and a for treatment of PAH in Europe and the US molecular weight of 378.42. It contains a and its therapeutic efficacy has been single chiral center determined to be the (S) demonstrated in several randomized, 73,74 configuration and has the following double-blind, placebo-controlled studies. structural formula: Ambrisentan was approved for sale by the U.S. Food and Drug Administration (FDA) on June 15, 2007 for the once-daily treatment of pulmonary arterial hypertension.75-77 It was later approved by the European Medicines Agency for use in the EU on April 2008.78 Ambrisentan had previously been designated an orphan drug by both the FDA and the European Commission, in August 2004 and May 2005 respectively. Clinical data The initial 3,3-diphenyl propionic Clinical trials with ambrisentan have acid based ERAs from BASF/Knoll were been performed since 2001 (Table discovered by screening of BASF’s 3).However, the initial Phase I trials in chemical library for compounds that bind to patients with cardiovascular disease and recombinant human ETA receptor revealed renal failure were mentioned only in the two diphenyl propionic acid derivates, reports of Abbott Laboratories but no data which were originally designed as from these trials were published. Similarly, herbicides.79 Modification of this structure
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X the initial Phase II trials, conducted by LETAIRIS and the geographic region of the Myogen since 2001, in patients with investigational sites. ARIES-1 compared hypertension, renal failure, cardiac failure, once-daily doses of 5 mg and 10 mg or cardiovascular disease were not reported LETAIRIS to placebo, while ARIES-2 in the literature. compared once-daily doses of 2.5 mg and 5 The first clinical data from the Phase mg LETAIRIS to placebo. In both studies, II trial with ambrisentan in patients with LETAIRIS or placebo was added to current PAH wasmade available in September 2003 therapy, which could have included a (Myogen website) and published in 2005. In combination of anticoagulants, diuretics, thisdose-blinded randomized trial, 64 calcium channel blockers, or digoxin, but patients suffering from PAH grades WHO II not epoprostenol, treprostinil, iloprost, or III were treated with ambrisentan (1, 2.5, bosentan, or sildenafil. The primary study 5, or 10 mgd), initially for 12 weeks. endpoint was 6-minute walk distance. In Afterwards, 54 of these patients participated addition, clinical worsening, WHO in an optional open labeled extension period functional class, dyspnea, and SF-36® of 12 weeks. At the end of this extension Health Survey were assessed. period the medication was further continued Patients had idiopathic or heritable in 44 patients. Furthermore, the 6 minutes PAH (64%) or PAH associated with walk distance,which is a standard functional connectivetissue diseases (32%), HIV parameter in PAH, significantly increased in infection (3%), or anorexigen use (1%). about 30% of patients during the initial 12 There were nopatients with PAH associated weeks and in 50% during the subsequent with congenital heart disease. Patients had open label period. An improvement of the WHO functional class I (2%), II (38%), III hemodynamic parameters was also (55%), or IV (5%) symptoms at baseline. observed. The mean age of patients was 50 years, 79% The safety and efficacy of ambrisentan of patients were female, and 77% were were assessed in two 12-week, randomized, Caucasian. Submaximal Exercise Ability doubleblind, placebo-controlled studies Results of the 6-minute walk distance at 12 involving 393 patients with PAH. weeks for the ARIES-1 studies are shown in Ambrisentan or placebo was added to Table 4 and Figure 3. current therapy, which could have included Although data describing the a combination of anticoagulants, diuretics, selectivity of ambrisentan for the ETA calcium-channel blockers or digoxin, but not receptor vary between 29:1 83 to >4000:1 84 epoprostenol, treprostinil, iloprost, bosentan depending on the assay cited, the drug is or sildenafil. One trial (ARIES-1) compared considered a selective ETA receptor once-daily oral doses of 5 mg and 10 mg antagonist.85,86 Ambrisentan is a relatively ambrisentan to placebo, and another selective antagonist of the ETA receptor. A (ARIES-2) compared once-daily doses of Phase-II dose-ranging study supported the 2.5 mg and 5 mg ambrisentan to placebo. efficacy and safety of ambrisentan in The primary end point in both studies was a patients with PAH, and subsequently two 6-minute walk distance.82 pivotal Phase-III clinical trials of Two 12-week, randomized, double- ambrisentan in PAH confirmed these blind, placebo-controlled, multicenter findings. Ambrisentan belongs to the group studies wereconducted in 393 patients with of carboxylic ERAs which unlike PAH (WHO Group 1). The two studies were sulfonamide-based ERAs – are devoid of identical indesign except for the doses of hepatotoxicity. In fact, patients on ERAs
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X with elevated liver function tests on plasma concentrations in PAH, ambrisentan sulfonamide-based ERAs such as bosentan has higher receptor occupancy with ETA ( or sitaxentan have been successfully 90%), than ETB ( 10%). Despite this, the switched to ambrisentan.87,88 Positive results reported selectivity of ambrisentan for ETA were recently published from a phase II of only 77/1,93 is somewhat less than the double-blind, dose-ranging study of generally accepted ratio needed for the ambrisentan 1mg, 2.5mg, 5mg or 10mg qualification as a selective ETA receptor once-daily for six months in patients with antagonist. Furthermore, significant PAH. increases in plasma ET-1 levels have been Ambrisentan is indicated for use in reported 2 hours after ingestion of the treatment of pulmonary arterial ambrisentan suggesting at least some hypertension (PAH) World Health functional antagonism of ETB in vivo.94,95 Organization (WHO) group 1 in patients with WHO class II or III symptoms to Pharmacokinetics of ambrisentan improve exercise capacity and delay clinical worsening.89 High-throughput screening led The pharmacokinetics of to the identification of nonpeptidic ambrisentan (S-ambrisentan) in healthy propionic acid derivatives with potent subjects are dose proportional. The antagonist activity against the ETA bioavailability of orally administered receptor7. Ambrisentan is a propionic acid ambrisentan in dogs is about 90% and its derivative that has a high selectivity for the duration of action is longer than 6 hr. In a ETA receptor versus the ETB receptor 90 Phase II clinical investigation, in patients whereas the other FDA-approved suffering from PAH, plasma levels of endothelin-receptor antagonist, bosentan, ambrisentan increased rapidly after oral affects both receptors.91 administration of the drug and reached C- Ambrisentan is developed as an max between 1.7 and 3.3 hr. The mean ETA receptor antagonist with a high elimination half-time was between 9 and 15 potency, high oral bioavailability, and long hr. In vitro studies indicate that ambrisentan half life suitable for once a day dosing.92 is a substrate of P-gp. Ambrisentan is highly Ambrisentan is available as 5 mg and 10 mg bound to plasma proteins (99%). The film-coated tablets for once daily oral elimination of ambrisentan is predominantly administration. The tablets include the by non-renal pathways, but the relative following inactive ingredients: contributions of metabolism and biliary croscarmellose sodium, lactose elimination have not been well monohydrate, magnesium stearate and characterized. The mean oral clearance of microcrystalline cellulose. Ambrisentan is a ambrisentan is 38 mL/min and 19 mL/min high affinity (Ki=0.011 nM) ETA receptor in healthy subjects and in PAH patients, antagonist with a high selectivity for the respectively. ETA versus ETB receptor (>4000-fold). The The chemical composition of clinical impact of high selectivity for ETA is ambrisentan, also known as LU 208075 or not known. Ambrisentan has slightly more BSF 208075, is C22H22N2O4, and its selectivity for the ET-A compared with the molecular weight is 378.4 g/mol. Another ET-B receptor (selectivity ratio, 77:1) than significant difference from bosentan is the bosentan (20:1); however, the clinical drug interaction profile. Bosentan is both a relevance of this difference in selectivity is substrate and an inducer of CYP2C9 and unknown. At therapeutically relevant CYP3A4, while ambrisentan is a substrate only for CYP2C19 and CYP3A4, as well as
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P-glycoprotein and organic anion transport with caution in patients receiving protein. concomitant cyclosporine. Cyclosporine is a Ambrisentan is a specific inhibitor of strong inhibitor of P-glycoprotein, OATP, endothelin A receptors, while bosentan and CYP3A4, therefore, ambrisentan inhibits both endothelin A and endothelin B; exposure may be increased with although selectivity may have theoretical concomitant cyclosporine administration. advantages, these advantages remain to be Caution is also advised when ambrisentan is proven.96,97 Ambrisentan is a white to off- coadministered with strong CYP3A and white, crystalline solid. It is a carboxylic 2C19 inhibitors, or inducers of P- acid with a pKa of 4.0. Ambrisentan is glycoprotein, CYP-450 enzymes, or UGTs. practically insoluble in water and in aqueous The interaction of ambrisentan and solutions at low pH. Solubility increases in warfarin was evaluated in 22 healthy aqueous solutions at higher pH. In the solid volunteers, who were given a single 25-mg state ambrisentan is very stable, is not oral dose of warfarin before and after 8 days hygroscopic, and is not light sensitive. of oral ambrisentan 10 mg/d.103 A 2-period Steady-state is achieved after 3–4 days of crossover study was conducted in 19healthy once-daily oral dosing with ambrisentan, adults to evaluate the interaction between and the pharmacokinetics of multiple doses sildenafil and ambrisentan.104 During the (ie, steady-state ambrisentan) are consistent first period, 19 healthy volunteers were with observations after a single dose.98 The given an oral dose of ambrisentan 10 mg steady-state elimination half-life of before and after receiving 7 days of oral ambrisentan in PAH patients is sildenafil 20 mg TID. During the second approximately 15 hours for the 5 mg dose, period of the study, the same volunteers providing the rationale for once-daily were given a single oral dose of sildenafil 20 dosing.99 In vitro data indicate that the mg before and after receiving 7 days of oral metabolism of ambrisentan is affected by ambrisentan 10 mg/d. The Cmax and AUC cytochrome P450 (CYP) 3A4 and 2C19 of sildenafil and ambrisentan were not isozymes, as well as by strong inhibitors of significantly changed. No dose adjustment is P-glycoprotein.100 required whenthe 2 agents are coadministered. Drug Interaction In a Phase 2, dose-ranging study, Potential interactions have not been prothrombin time, international normalized well characterized. Based on in vitro data, ratio, and anticoagulant dose were interactions with P-glycoprotein, OATP, unaffected by ambrisentan treatment.105 CYP3A4, and CYP2C19 inhibitors, and Similar results were reported for warfarin- UGTs are anticipated. Current sulfonamide- type anticoagulant dosing in the Phase 3 class ERAs developed for the treatment of ambrisentan trials.106 These data suggest that PAH are associated with potentially dosage adjustmentof warfarin is not needed significant drug-drug interactions. Bosentan during concomitant ambrisentan therapy. induces the cytochrome P450 isoenzymes Ambrisentan received FDA CYP2C9 and CYP3A4 and may decrease approval in June 2007. It is available as 5 the systemic exposure of other drugs that 101 and 10 mg tablets packaged in 30-count share this metabolic pathway. Similarly, blister packs. Ambrisentan tablets should be sitaxsentan inhibits the activity of CYP2C9, stored at 25°C (77°F), with excursions thereby increasing systemic exposure to permitted between 15° and 30°C (59° and drugs metabolized by this cytochromeP450 86°F). isozyme.102 Ambrisentan should be used
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Contraindication LETAIRIS or underlying heart failure, and the possible need for specific treatment or Ambrisentan is contraindicated in patients discontinuation of LETAIRIS therapy. who are pregnant or may become Ambrisentan use is not recommended in pregnant.Ambrisentan may cause fetal harm patients with moderate or severe hepatic when administered to a pregnant woman. function impairment. Ambrisentan should Teratogenicity is a class effect of endothelin be used with caution in patients with mild receptor antagonists. Ambrisentan is in hepatic function impairment. Pregnancy Category X. Teratogenicity has been observed in animal models and is a Adverse Reactions class effect of endothelin receptor antagonists. In animal studies, ambrisentan The most frequently reported adverse was teratogenic at oral doses of ≥15 mg/kg reactions included peripheral edema, nasal per day in rats and ≥7 mg/kg per day in congestion, sinusitis, flushing, palpitations, rabbits.107 It is recommended that women abdominal pain, and constipation. The who are taking ambrisentan not breastfeed. majority of the adverse reactions were classified as mild to moderate in severity Warnings and Precautions and only the incidence of nasal congestion was dose dependent. Hepatic toxicity has been observed with ambrisentan, bosentan, and sitaxsentan. Safety Ambrisentan has been observed to cause elevation of liver aminotransferases to at Ambrisentan was generally safe and least 3 times the upper limit of normal well tolerated in allthe PAH clinical studies. (ULN) in 0.8% of patients in 12-week The most frequently reportedadverse events ambrisentan studies and 2.8% of patients in during the Phase 2, dose-ranging study were long-term, open-label studies lasting up to 1 peripheral edema, nasal congestion, upper year. Ambrisentan should be avoided in respiratory tract infection, headache, patients with elevated aminotransferases flushing, and nausea and did not appear to (greater than three times the ULN) at be dose related. Ambrisentan was well baseline. Reductions in hemoglobin and tolerated throughout the 1-year extension study, with no emergent safety signals hematocrit have been observed within the 108 first few weeks of ambrisentan therapy. apparent during long-term therapy. More than 15% reductions in hemoglobin Liver abnormalities have been from baseline resulting in levels below the associated with the sulfonamide- class lower limit of normal occurred in 7% of ERAs and to date necessitate monthly liver patients treated with ambrisentan in clinical function testing (LFT).Alteration of liver trials (10% in the patients treated with 10 enzymes (mostly aminotransaminases) mg) compared with 4% of placebo-treated occured only in a few patients treated with patients. Hemoglobin monitoring is ambrisentan. The incidence of this side recommended during ambrisentan therapy. effect with ambrisentan appearsto be lower than with ET receptor antagonists with a Mild to moderate peripheral edema has been 109-111 observed during ambrisentan therapy. If pyrimidine structure, like bosentan. clinically significant fluid retention Also, no clinically relevant increase in liver develops, with or without associated weight enzymes was reported in the clinical trials gain, further evaluation should be with darusentan. It is, therefore, conceivable undertaken to determine the cause, such as that in patients treated with diphenyl propionic acid derivatives, like ambrisentan
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X or darusentan, this effect is caused by the receptor blockade (i.e. ETA vs. ETA/ETB). cytochrome p450 independent metabolism. Finally, the potential benefit of endothelin Serious events of liver toxicity in patients converting enzyme inhibition has yet to be treated with ET receptor antagonists have explored in PAH. only been reported in a few cases and after long term therapy. Conclusion In comparison with other ET- Ambrisentan offers an alternative to receptor antagonists ambrisentan appeared bosentan therapy. Ambrisentan is dosed to have a favorable efficacy to safety ratio in once daily, rather than twice daily like patients with PAH. In contrast to bosentan, bosentan. It may be associated with a lower ambrisentan has demonstrated a lower incidence of liver toxicity; however, close incidence of acute hepatotoxicity in the monitoring is still necessary. The choice of Phase 2 and 3 clinical trials. During the drug is dependent on a variety of factors, Phase 2, 24-week study, 2 (3%) patients including the approval status, route of experienced elevations in hepatic administration, side effect profile, patient aminotransferases >3 × ULN that required preference, and the physician’s experience dose reduction or drug discontinuation; an and clinical judgment. Ambrisentan is a additional 2 patients had isolated elevations selective ETA receptor antagonist that that were unconfirmed upon retest and appears to provide significant clinical required no change in treatment. benefit in the treatment of patients with Summary PAH. In Phase 2 and 3 clinical trials, ambrisentan improved exercise capacity, In summary, ambrisentan, an ETA-selective dyspnea, time to clinical worsening, WHO receptor antagonist, seems to improve functional class, quality of life, and exercise capacity, symptoms, and cardiopulmonary hemodynamic parameters. hemodynamics in patients with WHO class Ambrisentan has an improved safety II to III PAH. Ambrisentan may have a very profile compared with sulfonamide-class favorable efficacy-to-safety ratio in patients ERAs with respect to the potential for with PAH, including a low incidence and hepatic toxicity and the potential for drug- severity of serum aminotransferase drug interactions with agents metabolized abnormalities that does not seem to be dose- by P450 enzymes such as warfarin and dependent. Phase III placebo-controlled sildenafil. Available clinical data suggest trials are currently on going to confirm these that ambrisentan will be successful in the initial results. A direct comparison of treatment of PAH. Several experimental and selective ETA- with dual ETAB-receptor clinical trials will be necessary to determine antagonists is necessary for selection of the the optimal ET-receptor antagonist profile best treatment. Endothelin 1 is clearly a key for the specific pathological application. mediator in the pathogenesis of PAH. Advances in basic knowledge of its role in Expert opinion pulmonary vascular remodelling have led to translational clinical studies in man. Thus, The pathogenesis of pulmonary endothelin receptor antagonists are now a hypertension (PH) is complex and cornerstone in the management of this multifactorial. Increased pulmonary arterial devastating condition. However, over the pressure (PAP) in patients with PH probably lifetimeof the clinical studies to date, there results from a combination of pulmonary are no obvious advantages of differential vasoconstriction, inward vascular wall
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X remodelling and in situ thrombosis. The vasodilatory ETB receptor on endothelial central role of endothelial dysfunction in the cells, in addition to preserving ET-1 initiation and progression of PH resulting in pulmonary clearance. the altered production of endothelial The ETA-selective ERA mediators has been increasingly recognised ambrisentan holds promise in advancing in PH. Of those local mediators, nitric oxide both the safety and convenience of oral (NO), prostacyclin (PGI2), serotonin (5-HT) PAH treatment. Ambrisentan, a once-daily and endothelin (ET) are among the best oral treatment, does not induce or inhibit studied and most commonly implicated in cytochrome P450 enzymes; therefore, the pathogenesis of pulmonary arterial ambrisentan may be preferable to other hypertension (PAH).Pulmonary arterial currently available ERAs when used in hypertension is a progressive and generally conjunction with other medications incurable disease that afflicts approximately prescribed for patients with PAH. In clinical 117 000 women and men in the United trials with ambrisentan, there appears to be a States and approximately the same number low risk for acute hepatotoxicity. An oral in the EU.112 However, despite an overall once-daily agent with a low risk for liver poor prognosis, long-term survival and function abnormalities and drug–drug higher quality of life are increasingly interactions could confer advantages to the achievable in patients with PAH. Advances agent’s use in combination regimens, a in treatment have closely followed current area of active investigation and identification and characterization of disease optimism. pathways such that novel treatments are Improved understanding of the available that affect the prostacyclin, nitric cellular processes involved in the oxide, and endothelin pathways. pathogenesis of PAH has allowed for Endothelin receptor antagonists identification of several prospective targets have emerged as a cornerstone of therapy for pharmacologic intervention, including for patients with PAH when used either as vasoactive intestinal peptide (VIP), platelet- monotherapy or, increasingly, as an integral derived growth factor (PDGF), voltage- component of novel combination gated potassium channels, 5- regimens.113-114 Because some drugs have a hydroxytryptamine (serotonin) transporter narrow therapeutic window or, alternatively, (SERT) and vascular endothelial growth have safety concerns, coadministered agents factor (VEGF), tyrosine kinase inhibitors, that exhibit pharmacologic interactions may Rho-kinase inhibitors, statins, drug limit the effectiveness or exacerbate drug combinations and apoptotic therapies such toxicity. Inthis context, potential drug-drug as dichloroacetate among others. It is not interactions are increasingly important in known which, if any, of these approaches selecting a treatment for use in combination. will benefit patients with PAH, and it is Given the significant role that ET-1 seems clear that well-designed, controlled clinical to play in the pathobiology of PAH, there is trials, similar to those used to test a strong rationale for the use of ERAs in the ambrisentan, will be required to measure treatment of PAH. A selective ETA receptor benefits and complications. Until that time, antagonist may afford us the opportunity of ambrisentan is a new drug with an excellent blocking the actions of ET-1 at the benefit-to-risk profile and should find predominant vasoconstrictor receptor significant usage in the treatment of PAH. subtype, that is, ETA receptor, while Experimental studies have shown permitting ongoing stimulation of the preliminary favourable effects of gene and
AJADD[1][4][2013]572-595 Wal et al______ISSN 2321-547X stem cell therapy in animal models of http://www.phassociation.org/page.aspx?pid pulmonary hypertension. First experiences =538. Accessed October 13, 2010. with these innovative approaches in patients 7. Badesch DB, Champion HC, Sanchez MA, with PAH have been planned. By et al. 2009.Diagnosis and assessment of identifying the genes and gene variants that pulmonary arterial hypertension. J Am Coll Cardiol,54(suppl 1):S55-S66. determine individual disease susceptibility, 8. Chan SY, Loscalzo J. 2008. Pathogenic we might be able to identify patients in mechanisms of pulmonary arterial preclinical stages of disease as well as allow hypertension. J Mol Cell Cardiol, 44:14–30. for individualized therapies that are most 9. Granton J, Moric J. 2008. Pulmonary efficacious and least likely to cause side vasodilators–treating the right ventricle. effects. Ultimately, as these novel Anesthesiol Clin, 26:337–53, vii. therapeutic options are developed, 10. Pulmonary Hypertension Association: individualized treatment regimens will Newly Diagnosed. Available evolve. We hope that by further increasing at:http://www.phassociation.org/page.aspx? our understanding of the pathobiology of pid=538. Accessed October 13, 2010. PAH, we will one day be able to prevent and 11. Humbert, M. et al.2004.Treatment of pulmonary arterialhypertension. N. Engl. J. cure this disease. Med,351:1425–1436. 12. [No authors listed] Proceedings of the 3rd World Symposium on Pulmonary Arterial REFERENCES Hypertension. Venice,Italy, June 23-25, 2003. J Am Coll Cardiol. 2004 Jun 16;43(12 1. Hielsen LH, Lokkegaard E, Andreasen AH, Suppl S):1S-90S. et al. 2008.Using prescription registries to 13. Simonneau G, Robbins IM, Beghetti M, et define continuous drug use: how to fill gaps al. 2009.Updated clinicalclassification of between prescriptions. Pharmaco pulmonary hypertension. J Am Coll epidemiology and Drug Safety,17(4):384- Cardiol,54(suppl 1):S43-S54. 388. 14. Simonneau G, Galiè N, Rubin LJ, et 2. Newman JH, Fanburg BL, Archer SL, et al. al.2004.Clinical classification of pulmonary 2004. For the National Heart, Lung, and hypertension.J Am CollCardiol,43 (Suppl Blood Institute/Office of Rare Diseases. S):5S–12S. Pulmonary arterial hypertension: Future 15. Barst RJ, McGoon M, Torbicki A, et al. directions: Report of a National Heart, Lung, 2004.Diagnosis and differential assessment and Blood Institute/Office of Rare Diseases of pulmonary arterial hypertension. J Am workshop. Circulation,109:2947–2952. Coll Cardiol,43(12 Suppl S):40S–47S. 3. National Institute for Health and Clinical 16. Hoeper MM, Galie N, Simonneau G, et al. Excellence. Appraisal of the drug treatments 2002. New treatments for pulmonary arterial in Pulmonary Arterial Hypertension hypertension. Am J Respir Crit Care (PH).Pulmonary Arterial Hypertension Med,165:1209–1216. Association UK; 2007. 17. Ghofrani HA,Wiedemann R, Rose F, et al. 4. Letairis (ambrisentan). Learn about Letairis. 2002. Sildenafil for treatment of lung Available on: http://www.letairis.com. fibrosis and pulmonary hypertension: a Accessed on October 14, 2010. randomized controlled trial. Lancet, 5. Humbert M, Khaltaev N, Bousquet J, et al. 360:895–900. 2007. Pulmonary Hypertension: From an 18. Ghofrani HA, Rose F, Schermuly RT, et al. Orphan Disease to a Public Health Problem. 2003. Oral sildenafil as long-term adjunct Chest,312:365-467. therapy to inhaled iloprost in severe 6. Pulmonary Hypertension Association: about pulmonary arterial hypertension. J Am PAH. Available at: CollCardiol,42:158–164.
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84. Greene S, Nunley K, Weber S et al. ETA vs. hypertension: does selectivity matter? Eur ETB receptor selectivity of endothelin-1 Heart J. receptor antagonists. J Am CollCardiol 96. Letairis package insert. Foster City. CA: 2006; 47:307A. Gilead Sciences Inc.; 2007 June. 85. Barst RJ. Sitaxsentan: a selective 97. Tracleer package insert. South San endothelin-A receptor antagonist, for the Francisco. DA: Actelion Pharmaceuticals treatment of pulmonary arterial US, Inc; 2007 April. hypertension. Expert Opin Pharmacother 98. Rubin LJ, Dufton C, Gerber MJ. 2005b. 2007; 8:95–109. Ambrisentan for pulmonary arterial 86. Gilead U. Letairis® (Ambrisentan) Full hypertension. Future Cardiol, 1:1–8. Prescribing Information. 2008. 99. Oudiz R, Torres F, Frost A, et al. 2006. 87. Eriksson C, Gustavsson A, Kronvall T, Tysk ARIES-1: A placebo-controlled efficacy and C. Hepatotoxicity by bosentan in a patient safety study of ambrisentan in patients with with portopulmonary hypertension: a case- pulmonary arterial hypertension. Chest, report and review of the literature. J 130:121S. Gastrointestin Liver Dis 2011;20(1):77–80. 100. Letairis (ambrisentan) tablets for oral use. 88. McGoon MD, Frost AE, Oudiz RJ, Badesch Full prescribing DB, Galie N, Olschewski H, et al. information.http://www.letairis.com/downlo Ambrisentan therapy in patientswith ads/LETAIRIS_prescribing_information.pdf pulmonary arterial hypertension who .Accessed November 13, 2007. discontinued bosentan or sitaxsentan due to 101. Kenyon KW, Nappi JM. 2003. Bosentan liver function test abnormalities. Chest for the treatment of pulmonary arterial 2009;135(1):1229. hypertension. Ann Pharmacother, 37:1055– 89. Letairis [package insert]. Foster City, CA: 62. Gilead Sciences, Inc; 2007. 102. Barst RJ, Langleben D, Frost A, et al. 90. Riechers, H. et al. Discovery and 2004a. Sitaxsentan therapy for pulmonary optimization of a novel class of orally active arterial hypertension. Am J RespirCrit Care non peptidicendothelin-A receptor Med, 169:441–7. antagonists. J. Med. Chem. 39, 2123–2128 103. Gerber MJ, Dufton C, Pentikis H, et al. (1996). Ambrisentan has no clinically relevant effect 91. Rubin, L. J. et al. Bosentan therapy for on the pharmacokinetics or pulmonary arterial hypertension. N. Engl. J. pharmacodynamics of warfarin. Chest. Med. 346, 896–903 (2002). 2006;130(Suppl 4): 256S. Abstract. 92. Billman,G. E. (2002). Ambrisentan 104. Dufton C, Gerber M, Yin O, et al. No (Myogen). Curr Opin Investig Drugs clinically relevant pharmacokinetic 3,1483– 1486. interaction between ambrisentan and 93. Amberg W, Hergenroder S, Hillen H, et al. sildenafil. Chest. 2006;130(Suppl 4):254S. 1999. LU208075 and LU302146, two novel Abstract. ETA-selective endothelin receptor 105. Galie N, Badesch D, Oudiz R, et al. 2005a. antagonists: SAR of 3,3-diaryl propionic Ambrisentan therapy for pulmonaryarterial acid derivatives. International Conference hypertension. J Am CollCardiol, 46:529–35. on Endothelin, 6 October 10–13P. 106. Olschewski H, Galie N, Ghofrani HA, et al. 94. FDA/CDER Letairis (ambrisentan tablets) 2006. Ambrisentan improves exercise Clinical Pharmacology. Biopharmaceutics capacity and time to clinical worsening in Review 3:98–99.Accessed May 28 2008. patients with pulmonary arterial URL:http://www.fda.gov/cder/foi/nda/2007/ hypertension: Results of the ARIES-2 study. 022081s000_ClinPharmR_P3.pdf . Proc Am ThoracSoc, 3:A728. 95. Opitz, CF, Ewert R, Kirch W, et al. 2008. 107. Letairis (ambrisentan) tablets for oral use. Inhibition of endothelin receptors in the Full prescribing information. treatment of pulmonary arterial http://www.letairis.com/downloads/LETAIR
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IS_ prescribing_information.pdf. Accessed mediators after pancreas transplantation. November 13, 2007. Transplant Proc 2003;35:2137–2138. 108. Galie N, Keogh AM, Frost A, et al. 2005c. 116. Martignoni ME, Ceyhan GO, Ayuni E, et Ambrisentan long-term safety and efficacy al. Endothelin receptor antagonists are not in pulmonary arterial hypertension-one year beneficial in the therapy of acute follow up. Proc Am ThoracSoc, 2:A299. experimental pancreatitis. Langenbeck’s 109. Clozel M. Effects of bosentan on cellular Arch Surg 2004;389:184–192. processes involved in pulmonary arterial 117. Uhlmann D, Gabel G, Ludwig S, et al. hypertension: Do they explain the long-term Effects of ET(A) receptor antagonism on benefit? Ann Med 2003;35:605–613. proinflammatory gene expression and 110. Lee SH, Rubin LJ. Current treatment microcirculation following hepatic strategies for pulmonary arterial ischemiareperfusion. Microcirculation hypertension. J Intern Med 2005;258: 199– 2005;12:405–419. 215. 118. Uhlmann D, Gaebel G, Armann B, et al. 111. Mylona P, Cleland JG. Update of REACH- Attenuation of proinflammatory gene 1 and MERIT-HF clinical trials in heart expression and microcirculatory failure. Cardio.net Editorial Team. Eur J disturbances by endothelin A receptor Heart Fail 1999;1:197–200. blockade after orthotopic liver 112. Galie N, Manes A, Uguccioni L, et al. transplantation in pigs. Surgery Primary pulmonary hypertension: insights 2006;139:61–72. into pathogenesis from epidemiology. Chest. 119. Witzigmann H, Ludwig S, Escher E, et al. 1998;114(suppl):184S-94S. Administration of a selective endothelin-A 113. Hoeper MM, Markevych I, Spiekerkoetter receptor antagonist (BSF 208075) improves E, Welte T, Niedermeyer J. Goal-oriented hepatic warm ischemiareperfusion injury in treatment and combination therapy for pigs. Transplant Proc 2002;34: 2387–2388. pulmonary arterial hypertension. Eur Respir 120. Kirchengast M. Endothelin receptor J. 2005;26:858-863. blockade and in-stent restenosis. J 114. McLaughlin VV, Oudiz RJ, Frost A, et al. Cardiovasc Pharmacol 2001; 38(Suppl Randomized study of adding inhaled 2):S31–S34. iloprost to existing bosentan in pulmonary 121. Uhlmann D, Glasser S, Gaebel G, et al. arterial hypertension. Am J RespirCrit Care Improvement of postischemic hepatic Med. 2006;174:1257-1263. microcirculation after endothelin A receptor 115. Gabel G, Uhlmann D, Teupser D, et al. blockade — endothelin antagonism Influence of a selective endothelin(A) influences platelet-endothelium interactions. receptor antagonist on the quantitative J Gastrointest Surg 2005;9:187–197. mRNA expression and the immunohistochemistry of vasoactive
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Table 1. Current medications approved for the treatment of pulmonary arterial hypertension
Administration Generic name Trade name Drug class Data approved routes Epoprostenol Flolan Prostacyclin analogue Continous IV infusion 1995 Continous IV or SQ 2002 (SQ) Treprostnil Remodulin Prostacyclin analogue infusion 2004(IV) Nebulized inhalation Lloprost Ventavis Prostacyclin analogue 2004 6-9 times daily
Non-selective endothelin Bosentan Tracleer Oral twice daily 2001 Receptor antagonist
Selective endothelin Ambrisentan Letairis Oral once daily 2007 Receptor antagonist
Non-selective endothelin 2006 (Europe, Sitaxsentan Thelin Oral once daily Receptor antagonist Canada)
Phosphodiesterase Sildenafil Revatio Oral thrice daily 2005 Type 5 inhibitor Oral 1 to 3 times per Beraprost Prostacyclin analogue 1994 (Japan) day
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Table 2. Pulmonary Arterial Hypertension (PAH) Classification and Select Modifications to 2003 WHO Clinical Classification of PH
Updated 2008 World Health Organization (WHO) Clinical Classification of Pulmonary Hypertension (PH)
1. PAH • Idiopatic PAH • Heritable BMPR2, ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia), unknown • Drug- and toxin- induced • Associated with connective tissue diseases, HIV, portal hypertension, congenital heart disease, schistosomiasis, chronic hemolytic anemia • Persistent PH of the newborn • Pulmonary veno-occlusive disease and/or pulmonary capilaryhemangiomatosis
2. PH owing to left heart disease
3. PH owing to lung diseases and/or hypoxia • Other pulmonary disease with mixed restrictive and obstructive pattern
4. Chronic thromboembolic pulmonary hypertension
5. PH with unclear multifactorial mechanisms • Hematologic disorders: splenectomy, myeloprohferative disorders • Systemic disorders: sarcoidosis, vasculitis, neurofibromatosis • Metabolic disorders: thyroid disorders • Others: chronic renal failure on dialysis
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Table 3. Use of ambrisentan in animal models and clinical trials
PATHOLOGY MODEL REFERENCE
Animal Models
Ischemia reperfusion pancreas Pig 115
Ischemia reperfusion pancreas Rat 116
Ischemia reperfusion liver Pig 117,118,119
Ischemia reperfusion liver Rat 120
Angioplastyrestenosis Pig 121
Clinical Trials
Cardiovascular disease Phase I *not available (92)
Renal failure Phase I
Renal failure Phase II
Hypertension Phase II
Cardiac failure Phase II
Cardiovascular disease Phase II
PAH Phase II 105
PAH (ARIES-1) Phase III **Myogen(no data available)
PAH (ARIES-2) Phase III **Myogen (data available)
*Clinical trials, mentioned in the review by Billman et al. (92), no further details available. **Clinical trials, reported on the Myogen homepage, but not yet published.
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Table 4. Changes from Baseline in 6-Minute Walk Distance (meters)
ARIES-1 ARIES-2 Placebo Placebo 2.5mg 5mg (N=67) 10mg (N=67) 5mg (N=63) (N=67) (N=65) (N=64)
Baseline 342±73 340±77 342±78 343±86 347±84 355±84
Mean change from -8±79 23±83 44±63 -10±94 22±83 49±75 Baseline
Placebo-adjusted mean change from - 31 51 - 32 59 baseline
Placebo-adjusted mean change from - 27 39 - 30 45 baseline
p-valuea - 0.008 <0.001 - 0.022 <0.001
Mean ± standard deviation a. p-values are Wilcoxon rank sum test comparisons of LETAIRIS to placebo at Week 12 stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients.
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Figure.1. Schematic illustration of the endothelin system (redrawn with permission from http://www.nature.com/bjp/journal/v153/n6/fig_tab/0707516f1.html).ECE=endothelinconverting enzyme; EDRF=endothelium-derived relaxing factor; ET = endothelin; LDL = low-density lipoprotein.
Figure.2. Chemical scaffold of ambrisentan (LU 208075) ((+)-(S)-2-(4,6-dimethyl
pyrimidin-2-yloxy)-3-methoxy- 3,3-diphenyl-propionic acid) and the structurally similar darusentan (LU 1352521) ((+)-(S)-2(4,6-dimethoxy- pyrimidin-2-xyloxy)-3-methoxy-3,3- diphenyl-propionic acid).
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Figure.3. Mean Change in 6-Minute Walk Distance
Mean change from baseline in 6-minute walk distance in the placebo and LETAIRIS groups Values are expressed as mean ± standard error of the mean.
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