A New Drug for PAH: Clinical Pharmacology of Ambrisentan
In June 2007, the FDA approved ambrisentan (LETAIRIS) for the once-daily treatment of PAH to improve exercise capacity and delay clinical worsening.
Ambrisentan, a diphenyl propionic acid derivative ( Figure 1. PubChem CID:6918493), represents a valuable addition to the treatment alternatives for this orphan disease, which include prostacyclin (Flolan), inhaled nitric oxide, iloprost (a prostacyclin analog), sildenafil (a PDE5 inhibitor), and conventional Ca++ channel blockers (e.g., verapamil and nifedipine). Ambrisentan is orally active and similar to an existing drug, bosentan;[5] both are competitive inhibitors of endothelin receptors and are termed endothelin receptor antagonists (ERAs). However, bosentan lacks the receptor selectivity of ambrisentan. Ambrisentan exhibits ∼100-fold greater selectivity for endothelin receptor A (ETA) as compared to endothelin receptor B (ETB) [Ki = 0.6 nM for the human ETA receptor, 49 nM for the ETB receptor].[4] This moderate selectivity for the ET receptor may provide therapeutic advantages compared to bosentan. A common adverse effect of ERAs is the propensity to impair liver function in some patients. Thus, ambrisentan is not recommended for use in patients with moderate or severe hepatic impairment since it may cause additional liver damage.[6] Liver aminotransferase enzymes (ALT and AST) must be measured before initiation of therapy and at least monthly thereafter during therapy. The drug is an FDA category X pregnancy drug and is contraindicated in women who are or who may become pregnant. It is not known whether the drug is secreted in milk, therefore nursing mothers should not breastfeed while receiving the drug. Because of the risks of liver injury and birth defects, ambrisentan is only available through the Letairis Education and Access Program (LEAP); only prescribers and pharmacies registered with LEAP may prescribe and dispense the drug, and only patients enrolled in and meeting all conditions of LEAP may receive the drug (for enrollment information, call 866-663-5327).
Figure 1. (click image to zoom)
Adult dosing is initiated with 5 mg once daily, and if tolerated, dosing is increased to 10 mg once daily. Although early clinical trials showed no significant differences in beneficial effects using different doses of ambrisentan (1-10 mg) for patients with PAH,[7] the results of two recent clinical trials, ARIES-1 and ARIES-2, showed a dose-dependent improvement in 6-minute walk distance with once a day ambrisentan after 12 weeks. The absolute bioavailability of ambrisentan in humans is unknown, but is ∼90% in dogs.[7a] Bioavailability is unaffected by food. The drug is rapidly absorbed after oral administration with peak plasma concentrations occurring between 1.7 and 3.3 hours. The terminal half-life is about 15 hours, but after long-term daily dosing the effective half-life is about 9 hours.[49] At steady-state, mean trough concentrations of drug are ∼15% of mean peak concentrations. The drug is highly bound to plasma proteins and elimination is primarily by non-renal pathways. In vitro data indicate ambrisentan is a potential substrate of P-glycoprotein (P-gp), the Organic Anion Transport Protein (OATP), CYP3A4, CYP2C19, and uridine glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. Because in vivo data regarding drug interactions of ambrisentan with strong inhibitors or inducers of these transporters and metabolizing enzymes are very limited, caution is advised in co-administering drugs known to affect these entities. Concomitant administration of ambrisentan with warfarin in PAH patients had no effect on PT or INR; no adjustments in dose of warfarin or ambrisentan are required when co-administered.[49] Similarly, no dose adjustments are required when ambrisentan is co-administered with sildenafil.[49] Available in vitro and in vivo pharmacokinetic data indicate hepatic impairment is likely to prolong the elimination of ambrisentan. The drug is not recommended for patients with moderate to severe liver disease, and patients with mild pre-existing hepatic impairment may require reduced dosing. Based on clinical data, no dose adjustment is required in patients with mild to moderate renal impairment, but data in patients with severe renal disease are currently unavailable.[49]
Clinical studies have indicated ambrisentan and other ERAs cause a decrease in hemoglobin and hematocrit during the first few weeks of therapy, which then stabilizes. The cause of the decrease in hemoglobin is not known, but is not due to bleeding or hemolysis. Hemoglobin measurements are required prior to ambrisentan therapy and monthly thereafter. Another ERA class effect is peripheral edema, but this is also a consequence of PAH. In the clinical studies with ambrisentan, there was an increase in peripheral edema in patients taking 5 or 10 mg daily compared to placebo, but this was typically mild to moderate in severity. Most other adverse drug reactions seen in the clinical studies were mild to moderate; discontinuation of treatment due to adverse events other than those related to pulmonary hypertension was similar for drug and placebo (∼2%).[49]Pathophysiology of PAH
PAH is defined hemodynamically as a mean pulmonary arterial pressure of =25 mmHg with a pulmonary capillary wedge pressure of =15 mmHg, both measured at rest by right-heart catheterization. Elevated pulmonary arterial pressure in PAH patients is caused by increased pulmonary vascular resistance (PVR) as a result of severe pulmonary vascular remodeling, sustained pulmonary vasoconstriction, and in situ thrombosis in small arteries. Excessive vascular remodeling, manifested by obliteration of small arteries, muscularization of precapillary arterioles, intimal lesions and fibrosis, and the plexiform lesion, is the major contributor to the elevated PVR in most patients, while sustained vasoconstriction contributes to the elevated PVR in 15-20% of PAH patients. Vasoconstriction, by itself, is also a stimulus of pulmonary artery smooth muscle cell hypertrophy and hyperplasia. Loss of pulmonary vascular compliance and increased PVR due to pulmonary vascular remodeling leads to progressively pronounced pulmonary hypertension and has indeed been found to be the predominate pathological finding in idiopathic PAH.[1]Endothelin and Endothelin Receptors in PAH
Endothelin (ET) is a 21-amino acid peptide exhibiting three isoforms ET-1, ET-2, and ET-3 ( Figure 2, Figure 3, PDB ID: 1EDN). ET-1 is a potent vasoconstrictor, mitogen, and proinflammatory mediator. In the pulmonary circulation, increased ET-1 plasma levels correlate with changes in arterial pressure.[9,10] In patients with PAH, the level of ET-1 in the plasma and pulmonary microvasculature is increased as much as 10-fold and its concentrations correlate with pulmonary artery pressure and severity of disease.[10-13] The actions of endothelins in the vasculature are mediated by at least three different G-protein coupled receptors, the ETA receptor and two ETB receptor subtypes, ETB1 and ETB2.[20,21] ETA receptors bind ET-1 and ET-2 with a higher affinity than ET-3 (order of potency: ET-1 = ET-2 > ET-3), while ETB receptors have similar affinities for all three endothelin isoforms (i.e., order of potency is ET-1 = ET-2 = ET-3). ETA and ETB are functionally expressed in various tissues with different proportions. There are at least two studies demonstrating that expression of smooth muscle cell ETB receptors is increased in PAH,[13,16] while other studies demonstrate that the endothelial ETB receptors are downregulated or dysfunctional.[17,18] Furthermore, the endothelial ETB receptor-mediated ET clearance remains intact in patients with idiopathic PAH, and only modestly reduced in patients with PAH associated with connective tissue diseases (e.g., scleroderma).[19] These studies seem to suggest that increased ET concentration in the plasma and lung tissue serves as an important stimulus for sustained pulmonary vasoconstriction and excessive vascular remodeling in patients with PAH. Selective blockade of the endothelin receptors (e.g., ETA) that mediate contractile and mitogenic effects on PASMC, while maintaining (or preserving) the function of the endothelin receptors (e.g., ETB) that cause vasodilative effects and induce ET-1 clearance, is therefore a good strategy for designing therapeutic approaches for patients with PAH, and may offer more benefits than nonselective ETA/ETB antagonists.
Figure 2. (click image to zoom)
Amino acid sequence of ET-1. Dotted lines show arrangement of intramolecular disulfide bonds.
Figure 3. (click image to zoom)
The 3-D structure of human ET-1 determined by x-ray crystallography.
Printer- Friendly Email ThisReferencesRubin LJ: Primary pulmonary hypertension. N Engl J Med 336:111-117, 1997 8988890Runo JR, Loyd JE: Primary pulmonary hypertension. Lancet 361:1533-1544, 2003 12737878Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S-12S, 2004 15194173Billman GE: Ambrisentan (Myogen). Curr Opin Investig Drugs 3:1483-1486, 2002 12431023Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896-903, 2002 11907289Langleben D: Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Clin Chest Med 28:117-125, 2007 17338931Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, Frost AE, Zwicke D, Naeije R, Shapiro S, Olschewski H, Rubin LJ: Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 46:529-535, 2005 16053970Vatter H, Seifert V: Ambrisentan, a Non-peptide Endothelin Receptor Antagonist, Cardiovasc Drug Rev 24:63-76, 2006 16939634Hishikawa K, Nakaki T, Marumo T, Hayashi M, Suzuki H, Kato R, Saruta T: Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. J Clin Invest 93:1975-1980, 1994 8182128Morganti A, Marana I, Airoldi F, Alberti C, Nador B, Palatresi S: Plasma endothelin levels: a meaningless number? J Cardiovasc Pharmacol 35:S21-S23, 2000Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ: Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732-1739, 19938497283Stewart DJ, Levy RD, Cernacek P, Langleben D: Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 114:464-469, 19911994793Wagner OF, Vierhapper H, Gasic S, Nowotny P, Waldhausl W: Regional effects and clearance of endothelin-1 across pulmonary and splanchnic circulation. Eur J Clin Invest 22:277-282, 19921499643Bauer M, Wilkens H, Langer F, Schneider SO, Lausberg H, Schafers HJ: Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 105:1034-1036, 200211877350Ivy DD, Le Cras TD, Horan MP, Abman SH: Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension. Am J Physiol 274:L535-541, 1998Gomez AP, Moreno MJ, Iglesias A, Coral PX, Hernandez A: Endothelin 1, its endothelin type A receptor, connective tissue growth factor, platelet-derived growth factor, and adrenomedullin expression in lungs of pulmonary hypertensive and nonhypertensive chickens. Poult Sci 86:909-916, 200717435025Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, Wharton J: ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 165:398-405, 200211818328Clozel M: Endothelin receptor antagonist. Heart Fail Rev 6:249-251, 200111447299Clozel M: Effects of bosentan on cellular processes involved in pulmonary arterial hypertension: do they explain the long-term benefit? Ann Med 35:605-613, 200314708970Langleben D, Dupuis J, Langleben I, Hirsch AM, Baron M, Senecal JL, Giovinazzo M: Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension. Chest 129:689-695, 200616537869Levin ER: Endothelins. N Engl J Med 333:356-363, 19957609754Shyamala V, Moulthrop TH, Stratton-Thomas J, Tekamp-Olson P: Two distinct human endothelin B receptors generated by alternative splicing from a single gene. Cell Mol Biol Res 40:285-296, 19947866430Warner TD, Allcock GH, Corder R, Vane JR: Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF. Br J Pharmacol 110:777-782, 19938242251Kawanabe Y, Nauli SM: Involvement of extracellular Ca2+ influx through voltage-independent Ca2+ channels in endothelin-1 function. Cell Signal 17:911-916, 200515894164Brunner F, Bras-Silva C, Cerdeira AS, Leite-Moreira AF: Cardiovascular endothelins: essential regulators of cardiovascular homeostasis. Pharmacol Ther 111:508-531, 200616457892Warner TD, Mitchell JA, de Nucci G, Vane JR: Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit. J Cardiovasc Pharmacol 13 Suppl 5:S85-S88, 1989de Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, Vane JR: Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 85:9797-9800, 1988Wright CE, Fozard JR: Regional vasodilation is a prominent feature of the haemodynamic response to endothelin in anaesthetized, spontaneously hypertensive rats. Eur J Pharmacol 155:201-203, 19882907490Makino A, Kamata K: Elevated plasma endothelin-1 level in streptozotocin-induced diabetic rats and responsiveness of the mesenteric arterial bed to endothelin-1. Br J Pharmacol 123:1065-1072, 1998 9559887Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, Marumo F: Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 91:1367-1373, 19937682570Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ: Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 97:752-756, 19989498538Goto K, Hama H, Kasuya Y: Molecular pharmacology and pathophysiological significance of endothelin. Jpn J Pharmacol 72:261-290, 19969015736D'Orleans-Juste P, Claing A, Warner TD, Yano M, Telemaque S: Characterization of receptors for endothelins in the perfused arterial and venous mesenteric vasculatures of the rat. Br J Pharmacol 110:687-692, 1993Warner TD: Simultaneous perfusion of rat isolated superior mesenteric arterial and venous beds: comparison of their vasoconstrictor and vasodilator responses to agonists. Br J Pharmacol 99:427-433, 19902328405White DG, Cannon TR, Garratt H, Mundin JW, Sumner MJ, Watts IS: Endothelin ETA and ETB receptors mediate vascular smooth-muscle contraction. J Cardiovasc Pharmacol 22 Suppl 8:S144-148, 1993Makino A, Kamata K: Time-course changes in plasma endothelin-1 and its effects on the mesenteric arterial bed in streptozotocin-induced diabetic rats. Diabetes Obes Metab 2:47-55, 200011220354Hay DW, Luttmann MA, Beck G, Ohlstein EH: Comparison of endothelin B (ETB) receptors in rabbit isolated pulmonary artery and bronchus. Br J Pharmacol 118:1209-1217, 19968818345Bonvallet ST, Oka M, Yano M, Zamora MR, McMurtry IF, Stelzner TJ: BQ123, an ETA receptor antagonist, attenuates endothelin-1-induced vasoconstriction in rat pulmonary circulation. J Cardiovasc Pharmacol 22:39-43, 19937690094MacLean MR, McCulloch KM, Baird M: Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles. J Cardiovasc Pharmacol 23:838-845, 19947521470MacLean MR, McCulloch KM, Baird M: Effects of pulmonary hypertension on vasoconstrictor responses to endothelin-1 and sarafotoxin S6C and on inherent tone in rat pulmonary arteries. J Cardiovasc Pharmacol 26:822-830, 19958637198Soma S, Takahashi H, Muramatsu M, Oka M, Fukuchi Y: Localization and distribution of endothelin receptor subtypes in pulmonary vasculature of normal and hypoxia-exposed rats. Am J Respir Cell Mol Biol 20:620-630, 199910100993Fukuroda T, Kobayashi M, Ozaki S, Yano M, Miyauchi T, Onizuka M, Sugishita Y, Goto K, Nishikibe M: Endothelin receptor subtypes in human versus rabbit pulmonary arteries. J Appl Physiol 76:1976-1982, 19948063659McCulloch KM, Docherty CC, Morecroft I, MacLean MR: EndothelinB receptor-mediated contraction in human pulmonary resistance arteries. Br J Pharmacol 119:1125-1130, 19968937714Sugawara F, Ninomiya H, Okamoto Y, Miwa S, Mazda O, Katsura Y, Masaki T: Endothelin-1-induced mitogenic responses of Chinese hamster ovary cells expressing human endothelinA: the role of a wortmannin-sensitive signaling pathway. Mol Pharmacol 49:447-457, 19968643084Henry PJ: Endothelin-1 (ET-1)-induced contraction in rat isolated trachea: involvement of ETA and ETB receptors and multiple signal transduction systems. Br J Pharmacol 110:435-441, 19938220905Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M: Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 199:1461-1465, 19948147891Opgenorth TJ, Wessale JL, Dixon DB, Adler AL, Calzadilla SV, Padley RJ, Wu-Wong JR: Effects of endothelin receptor antagonists on the plasma immunoreactive endothelin-1 level. J Cardiovasc Pharmacol 36:S292-296, 2000Reinhart GA, Preusser LC, Burke SE, Wessale JL, Wegner CD, Opgenorth TJ, Cox BF: Hypertension induced by blockade of ETB receptors in conscious nonhuman primates: role of ETA receptors. Am J Physiol Heart Circ Physiol 283:H1555-1561, 2002Strachan FE, Spratt JC, Wilkinson IB, Johnston NR, Gray GA, Webb DJ: Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. Hypertension 33:581-585, 19999931169Gilead Sciences, Inc.: Prescribing Information for LETAIRIS. www.gilead.com/pdf/letairis_pi.pdf. Accessed 01/08/08.Hilal-Dandan R, Ramirez MT, Villegas S, Gonzalez A, Endo-Mochizuki Y, Brown JH, Brunton L: Endothelin ETA receptor regulates signaling and ANF gene expression via multiple G protein-linked pathways. Am J Physiol 272:H130-H137,1997Hilal-Dandan R, Means C, Gustafsson Å, Morissette M, Adams J, Brunton LL and Brown JH:Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho. J Mol Cell Cardiol 36; 481-493, 2004Hilal-Dandan R, Villegas S., Gonzalez A and Brunton L: The quasi-irreversible nature of endothelin binding and G protein-linked signaling in cardiac myocytes. J Pharmacol Exp Therap 281:267-273,1997
AccessMedicine from McGraw-Hill. 2008; ©2008 The McGraw-Hill Companies
All rights reserved. From Tintinalli's Emergency Medicine
This is a part of article Ambrisentan: A New Drug For Pulmonary Arterial Hypertension Taken from "Purchase Sildenafil Citrate" Information Blog
