A Medicines Management Review of Treprostinil Sodium (Remodulin) in Pulmonary Arterial Hypertension

Abstract

Executive Summary
Infusions of prostacyclin or its analogues are part of the treatment strategy for moderate to severe pulmonary arterial hypertension. Treprostinil is a stable prostacyclin analogue with a half-life of over four hours that can be administered either by inhalation or by an intravenous (IV) or subcutaneous (SC) infusion. During the pivotal trial for SC treprostinil, the incidence of infusion-site pain led to dose reductions or limitations in uptitration, resulting in underdosing of treprostinil. As a result, improvements in functional ability at 12 weeks with treprostinil were modest. However, the mean dose achieved was far short of the target dose, and an analysis of the dose quartiles revealed that patients receiving >13ng/kg/min had comparable improvement to those receiving other therapies. Moreover, current knowledge suggests that pain associated with treprostinil is not directly related to the dose. Long-term experience has led to improved and more rapid upward dose titration of treprostinil, resulting in better pain management and better outcomes. Long-term survival in patients remaining on treprostinil therapy appears similar to that achieved with the current gold standard™, epoprostenol. An IV formulation of treprostinil has recently been approved in the US, Canada, Switzerland, Israel and much of South America. IV infusion of treprostinil offers an alternative for patients who are intolerant to SC delivery or to first-line prostacyclin therapy. Increasingly, published evidence suggests that with good patient preparation and support, treprostinil delivered subcutaneously or intravenously is an effective prostanoid to improve PAH outcome.

Disclosure: No sources of funding were used to assist in the preparation of this review. United Therapeutics provided a non-binding review of this article.

Touch Briefings wishes to thank Professor Vachiery for reviewing this article for scientific accuracy.

References
  1. Simonneau g, robbins IM, Beghetti M, et al., Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol, 2009;54:S43├óÔé¼ÔÇ£54.
  2. Badesch DB, Abman SH, Simonneau g, et al., Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines, Chest, 2007;131:1917├óÔé¼ÔÇ£28.
  3. galie N, Hoeper MM, Humbert M, et al., guidelines for the diagnosis and treatment of pulmonary hypertension, Eur Respir J, 2009;34:1219├óÔé¼ÔÇ£63.
  4. NPHC, Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland, Thorax, 2008;63(Suppl. 2):ii1├óÔé¼ÔÇ£ii41.
  5. Peacock AJ, Murphy Nf, McMurray JJ, et al., An epidemiological study of pulmonary arterial hypertension, Eur Respir J, 2007;30:104├óÔé¼ÔÇ£9.
  6. Humbert M, Sitbon o, Chaouat A, et al., Pulmonary arterial hypertension in france: results from a national registry, Am J Respir Crit Care Med, 2006;173:1023├óÔé¼ÔÇ£30.
  7. rich S, Dantzker Dr, Ayres SM, et al., Primary pulmonary hypertension. A national prospective study, Ann Intern Med, 1987;107:216├óÔé¼ÔÇ£23.
  8. Thenappan T, Shah SJ, rich S, et al., A USA-based registry for pulmonary arterial hypertension: 1982├óÔé¼ÔÇ£2006, Eur Respir J, 2007;30:1103├óÔé¼ÔÇ£10.
  9. Willers eD, Newman JH, Loyd Je, et al., Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension, Am J Respir Crit Care Med, 2006;173:798├óÔé¼ÔÇ£802.
  10. rubin LJ, Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines, Chest, 2004;126:7S├óÔé¼ÔÇ£10S.
  11. Nauser TD, Stites SW, Diagnosis and treatment of pulmonary hypertension, Am Fam Physician, 2001;63: 1789├óÔé¼ÔÇ£98.
  12. Barst rJ, Mcgoon M, Torbicki A, et al., Diagnosis and differential assessment of pulmonary arterial hypertension, J Am Coll Cardiol, 2004;43:40S├óÔé¼ÔÇ£7S.
  13. Shafazand S, goldstein MK, Doyle rL, et al., Healthrelated quality of life in patients with pulmonary arterial hypertension, Chest, 2004;126:1452├óÔé¼ÔÇ£9.
  14. Taichman DB, Shin J, Hud L, et al., Health-related quality of life in patients with pulmonary arterial hypertension, Respir Res, 2005;6:92.
  15. Humbert M, Morrell NW, Archer SL, et al., Cellular and molecular pathobiology of pulmonary arterial hypertension, J Am Coll Cardiol, 2004;43:13S├óÔé¼ÔÇ£24S.
  16. giaid A, Yanagisawa M, Langleben D, et al., expression of endothelin-1 in the lungs of patients with pulmonary hypertension, N Engl J Med, 1993;328:1732├óÔé¼ÔÇ£9.
  17. Langleben D, DeMarchie M, Laporta D, et al., endothelin- 1 in acute lung injury and the adult respiratory distress syndrome, Am Rev Respir Dis, 1993;148:1646├óÔé¼ÔÇ£50.
  18. Davie N, Haleen SJ, Upton PD, et al., eT(A) and eT(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells, Am J Respir Crit Care Med, 2002;165:398├óÔé¼ÔÇ£405.
  19. Herve P, Launay JM, Scrobohaci ML, et al., Increased plasma serotonin in primary pulmonary hypertension, Am J Med, 1995;99:249├óÔé¼ÔÇ£54.
  20. giaid A, Saleh D, reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension, N Engl J Med, 1995;333:214├óÔé¼ÔÇ£21.
  21. Christman BW, McPherson CD, Newman JH, et al., An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension, N Engl J Med, 1992;327:70├óÔé¼ÔÇ£75.
  22. Petkov V, Mosgoeller W, Ziesche r, et al., Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension, J Clin Invest, 2003;111:1339├óÔé¼ÔÇ£46.
  23. Jones DA, Benjamin CW, Linseman DA, Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades, Mol Pharmacol, 1995;48:890├óÔé¼ÔÇ£96.
  24. Tuder rM, Cool CD, geraci MW, et al., Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension, Am J Respir Crit Care Med, 1999;159:1925├óÔé¼ÔÇ£32.
  25. Benedict N, Seybert A, Mathier MA, evidence-based pharmacologic management of pulmonary arterial hypertension, Clin Ther, 2007;29:2134├óÔé¼ÔÇ£53.
  26. Badesch DB, McLaughlin VV, Delcroix M, et al., Prostanoid therapy for pulmonary arterial hypertension, J Am Coll Cardiol, 2004;43:56S├óÔé¼ÔÇ£61S.
  27. Barst rJ, rubin LJ, Long WA, et al., A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study group, N Engl J Med, 1996;334:296├óÔé¼ÔÇ£302.
  28. McLaughlin VV, Shillington A, rich S, Survival in primary pulmonary hypertension: the impact of epoprostenol therapy, Circulation, 2002;106:1477├óÔé¼ÔÇ£82.
  29. rubin LJ, Mendoza J, Hood M, et al., Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). results of a randomized trial, Ann Intern Med, 1990;112:485├óÔé¼ÔÇ£91.
  30. Badesch DB, Tapson Vf, Mcgoon MD, et al., Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial, Ann Intern Med, 2000;132:425├óÔé¼ÔÇ£34.
  31. Barst rJ, rubin LJ, Mcgoon MD, et al., Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin, Ann Intern Med, 1994;121:409├óÔé¼ÔÇ£15.
  32. olschewski H, ghofrani HA, Walmrath D, et al., Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis, Am J Respir Crit Care Med, 1999;160:600├óÔé¼ÔÇ£7.
  33. Hoeper MM, Schwarze M, ehlerding S, et al., Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue, N Engl J Med, 2000;342:1866├óÔé¼ÔÇ£70.
  34. olschewski H, Simonneau g, galie N, et al., Inhaled iloprost for severe pulmonary hypertension, N Engl J Med, 2002;347:322├óÔé¼ÔÇ£9.
  35. Channick rN, Simonneau g, Sitbon o, et al., effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study, Lancet, 2001;358:1119├óÔé¼ÔÇ£23.
  36. rubin LJ, Badesch DB, Barst rJ, et al., Bosentan therapy for pulmonary arterial hypertension, N Engl J Med, 2002;346:896├óÔé¼ÔÇ£903.
  37. Dupuis J, Hoeper MM, endothelin receptor antagonists in pulmonary arterial hypertension, Eur Respir J, 2008;31: 407├óÔé¼ÔÇ£15.
  38. Paul gA, gibbs JS, Boobis Ar, et al., Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension, Br J Clin Pharmacol, 2005;60:107├óÔé¼ÔÇ£12.
  39. Barst rJ, Langleben D, Badesch D, et al., Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan, J Am Coll Cardiol, 2006;47:2049├óÔé¼ÔÇ£56.
  40. Barst rJ, Langleben D, frost A, et al., Sitaxsentan therapy for pulmonary arterial hypertension, Am J Respir Crit Care Med, 2004;169:441├óÔé¼ÔÇ£7.
  41. Barst rJ, rich S, Widlitz A, et al., Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: openlabel pilot study, Chest, 2002;121:1860├óÔé¼ÔÇ£68.
  42. gali─é┬¿ N, olschewski H, oudiz rJ, et al., Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ArIeS) study 1 and 2, Circulation, 2008;117:3010├óÔé¼ÔÇ£19.
  43. Volibris, Summary of Product Characteristics, 2009. Available at: emc.medicines.org.uk/medicine/20848/
  44. Corbin JD, francis SH, Cyclic gMP phosphodiesterase-5: target of sildenafil, J Biol Chem, 1999;274:13729├óÔé¼ÔÇ£32.
  45. Manes A TB, galie N effects of sildenafil on growth and viability of cultured human pulmonary artery smooth muscle cells, J Am Coll Cardiol, 2003;41:223A.
  46. gali─é┬¿ N, ghofrani HA, Torbicki A, et al., Sildenafil citrate therapy for pulmonary arterial hypertension, N Engl J Med, 2005;353:2148├óÔé¼ÔÇ£57.
  47. Barst rJ, Brundage BH, ghofrani A, et al., Tadalafil improves exercise capacity, health related quality of life and delays time to clinical worsening in patients with symptomatic pulmonary arterial hypertension (PAH), Chest, 2008;134:s39003.
  48. gibbs S, recommendations on the management of pulmonary hypertension in clinical practice, Heart, 2001;86(Suppl. 1):I1├óÔé¼ÔÇ£13.
  49. McLaughlin VV, Archer SL, Badesch DB, et al., ACCf/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology foundation Task force on expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association, J Am Coll Cardiol, 2009;53:1573├óÔé¼ÔÇ£1619.
  50. remodulin, Prescribing Information, 2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2008/ 021272s008lbl.pdf
  51. Doran AK, Ivy DD, Barst rJ, et al., guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension, Int J Clin Pract Suppl, 2008;5├óÔé¼ÔÇ£9.
  52. Laliberte K, Arneson C, Jeffs r, et al., Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (remodulin) administered by the intravenous and subcutaneous route to normal volunteers, J Cardiovasc Pharmacol, 2004;44:209├óÔé¼ÔÇ£14.
  53. Simonneau g, Barst rJ, galie N, et al., Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebocontrolled trial, Am J Respir Crit Care Med, 2002;165:800├óÔé¼ÔÇ£4.
  54. rubenfire M, McLaughlin VV, Allen rP, et al., Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial, Chest, 2007;132:757├óÔé¼ÔÇ£63.
  55. Skoro-Sajer N, Lang IM, Harja e, et al., A clinical comparison of slow- and rapid-escalation treprostinil dosing regimens in patients with pulmonary hypertension, Clin Pharmacokinet, 2008;47:611├óÔé¼ÔÇ£18.
  56. gali─é┬¿ N, Seeger W, Naeije r, et al., Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension, J Am Coll Cardiol, 2004;43:81S├óÔé¼ÔÇ£8S.
  57. Lang I, gomez-Sanchez M, Kneussl M, et al., efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension, Chest, 2006;129:1636├óÔé¼ÔÇ£43.
  58. gomberg-Maitland M, Tapson Vf, Benza rL, et al., Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension, Am J Respir Crit Care Med, 2005;172:1586├óÔé¼ÔÇ£9.
  59. Vachiery JL, Hill N, Zwicke D, et al., Transitioning from i.v. epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension, Chest, 2002;121:1561├óÔé¼ÔÇ£5.
  60. Steffen rP, de la Mata M, The effects of I5AU8I, a chemically stable prostacyclin analog, on the cardiovascular and renin-angiotensin systems of anesthetized dogs, Prostaglandins Leukot Essent Fatty Acids, 1991;43:277├óÔé¼ÔÇ£86.
  61. McNulty MJ, Sailstad JM, Steffen rP, The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog, Prostaglandins Leukot Essent Fatty Acids, 1993;48:159├óÔé¼ÔÇ£66.
  62. McLaughlin VV, gaine SP, Barst rJ, et al., efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension, J Cardiovasc Pharmacol, 2003;41: 293├óÔé¼ÔÇ£9.
  63. Skoro-Sajer N, Bonderman D, Wiesbauer f, et al., Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension, J Thromb Haemost, 2007;5:483├óÔé¼ÔÇ£9.
  64. McSwain CS, Benza r, Shapiro S, et al., Dose proportionality of treprostinil sodium administered by continuous subcutaneous and intravenous infusion, J Clin Pharmacol, 2008;48:19├óÔé¼ÔÇ£25.
  65. Tapson Vf, gomberg-Maitland M, McLaughlin VV, et al., Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, openlabel, 12-week trial, Chest, 2006;129:683├óÔé¼ÔÇ£8.
  66. Hiremath J, Thanikachalam S, Parikh K, et al., exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial, J Heart Lung Transplant, 2010;29:137├óÔé¼ÔÇ£49.
  67. Sitbon o, Manes A, Jais X, et al., rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension, J Cardiovasc Pharmacol, 2007;49:1├óÔé¼ÔÇ£5.
  68. feldman JP, Chakinala M, Torres f, et al., Treprostinil sodium improves exercise capacity when addred to existing oral pulmonary arterial hypertension therapy, Chest, 2007;132(4):474b├óÔé¼ÔÇ£5b.
  69. Chua r, Keogh A, Combining treprostinil and sildenafil in the treatment of pulmonary hypertension, Intern Med J, 2005;35:684├óÔé¼ÔÇ£5.
  70. Benza rL, rayburn BK, Tallaj JA, et al., Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension: long-term efficacy and combination with bosentan, Chest, 2008;134:139├óÔé¼ÔÇ£45.
  71. Skoro-Sajer N, Lang I, Treprostinil for the treatment of pulmonary hypertension, Expert Opin Pharmacother, 2008;9:1415├óÔé¼ÔÇ£20.
  72. Ivy DD, Calderbank M, Wagner BD, et al., Closed-hub systems with protected connections and the reduction of risk of catheter-related bloodstream infection in pediatric patients receiving intravenous prostanoid therapy for pulmonary hypertension, Infect Control Hosp Epidemiol, 2009;30:823├óÔé¼ÔÇ£9.
  73. rector rS, Kubo SH, Cohn JN, Patients self-assessment of their congestive heart failure, Heart Failure, 1987;1: 198├óÔé¼ÔÇ£209.
  74. Minai oA, Chen H, Parambil J, et al., Safety, efficacy and treatment satisfaction following rapid switch from epoprostenol to iv treprostinil in stable pulmonary arterial hypertension patients, Am J Respir Crit Care Med, 2008;177: abstract 822.
  75. De Wet CJ, Affleck Dg, Jacobsohn e, et al., Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery, J Thorac Cardiovasc Surg, 2004;127:1058├óÔé¼ÔÇ£67.
  76. Highland KB, Strange C, Mazur J, et al., Treatment of pulmonary arterial hypertension: a preliminary decision analysis, Chest, 2003;124:2087├óÔé¼ÔÇ£92.
  77. einarson Tr, granton JT, Vicente C, et al., Costeffectiveness of treprostinil versus epoprostenol in patients with pulmonary arterial hypertension: a Canadian analysis, Can Respir J, 2005;12:419├óÔé¼ÔÇ£25.
  78. Narine L, Hague LK, Walker JH, et al., Cost-minimization analysis of treprostinil vs. epoprostenol as an alternate to oral therapy non-responders for the treatment of pulmonary arterial hypertension, Curr Med Res Opin, 2005;21:2007├óÔé¼ÔÇ£16.
  79. Appelbaum L, Yigla M, Bendayan D, et al., Primary pulmonary hypertension in Israel: a national survey, Chest, 2001;119:1801├óÔé¼ÔÇ£6.
  80. gaine SP, rubin LJ, Primary pulmonary hypertension, Lancet, 1998;352:719├óÔé¼ÔÇ£25.
  81. NICe Citizens™ Council report, Ultra orphan Drugs, 2004. Available at: www.nice.org.uk/niceMedia/pdf/Citizens_ Council_Ultraorphan.pdf
  82. NICe, Appraising orphan Drugs 2007. Available at: www.nice.org.uk/niceMedia/pdf/smt/120705item4.pdf
  83. Angus DC, Linde-Zwirble WT, Lidicker J, et al., epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care, Crit Care Med, 2001;29:1303├óÔé¼ÔÇ£10.
  84. Bates DW, Yu DT, Black e, et al., resource utilization among patients with sepsis syndrome, Infect Control Hosp Epidemiol, 2003;24:62├óÔé¼ÔÇ£70.
  85. edbrooke DL, Hibbert CL, Kingsley JM, et al., The patientrelated costs of care for sepsis patients in a United Kingdom adult general intensive care unit, Crit Care Med, 1999;27:1760├óÔé¼ÔÇ£67.
  86. Manns BJ, Lee H, Doig CJ, et al., An economic evaluation of activated protein C treatment for severe sepsis, N Engl J Med, 2002;347:993├óÔé¼ÔÇ£1000.
  87. D™Alonzo ge, Barst rJ, Ayres SM, et al., Survival in patients with primary pulmonary hypertension. results from a national prospective registry, Ann Intern Med, 1991;115:343├óÔé¼ÔÇ£9.
  88. Hinderliter AL, Willis PWt, Barst rJ, et al., effects of longterm infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study group, Circulation, 1997;95:1479├óÔé¼ÔÇ£86.
  89. Sitbon o, Humbert M, Nunes H, et al., Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival, J Am Coll Cardiol, 2002;40:780├óÔé¼ÔÇ£88.
  90. McLaughlin VV, genthner De, Panella M
    , et al., reduction in pulmonary vascular resistance with longterm epoprostenol (prostacyclin) therapy in primary pulmonary hypertension, N Engl J Med, 1998;338:273├óÔé¼ÔÇ£7.