Pulmonary Arterial Hypertension: Targeting Prostacyclin and Endothelin

Pulmonary arterial hypertension (PAH) affects between 15 and 50 million individuals.¹ Remodeling of the pulmonary vasculature, thrombi, and increased vascular resistance and pulmonary arterial pressure (over 25 mm Hg) lead to right heart failure and death if not treated.^1-4 PAH may be idiopathic or genetic, or caused by drugs and/or disease.1 The 3-year survival rate for idiopathic or heritable PAH is 74%.²

World Health Organization (WHO) functional classes range from least (class I) to most affected (class IV) based on functional compromise (including shortness of breath, fatigue, chest pain, and dizziness); 75% of patients are WHO functional class III/IV at diagnosis.³ Clinical presentation is usually related to right heart failure symptoms.⁴ Medications developed specifically for PAH include prostanoids (epoprostenol, treprostinil, and iloprost) and endothelin receptor antagonists (ERAs) (bosentan and ambrisentan).⁴

Prostanoids (Prostacyclin Vasodilators) Prostacyclin promotes vasodilation, but is decreased with PAH.² Prostanoids are direct vasodilators that inhibit platelet aggregation, cause smooth muscle relaxation, and may affect pulmonary remodeling and reduce inflammation.^2,4,5 Adverse effects (AEs) common to all prostanoids include headache, gastrointestinal disturbances, jaw pain, and flushing.² Consider using inhaled formulations to reduce systemic AEs.²

Epoprostenol was the first prostanoid.⁴ This drug improves symptoms, exercise capacity, hemodynamics, and survival (possibly), but it is complex to administer.^2,4,6 Because its short half-life (less than 6 minutes) necessitates an indwelling catheter for continuous infusion (increasing infection and thrombosis risk), pump failure could lead to deadly rebound pulmonary hypertension.^2,4,6 Close observation is needed during initiation/ titration because of potentially fatal acute pulmonary edema.² Flu-like symptoms are common.^2,4

Dosing starts at 2 ng/kg/min and increases to 10 to 16 ng/kg/min if tolerated.⁴ There are 2 formulations: the more stable (24 to 72 hours) arginine-mannitol excipient (Veletri) or the glycine-mannitol excipient (Flolan), which is only stable at room temperature for 8 hours (24 hours using cold packs).^2,5,6

Iloprost (Ventavis) is an inhaled prostanoid that improves exercise tolerance and symptoms, and slows deterioration.⁴ Although monotherapy works for about 17% of patients, over half lose efficacy within 1 year.^2,4 Iloprost is dosed at 2.5 to 5 mcg inhaled 6 to 9 times a day (every 2 hours while awake).^2,4,7 Hepatic impairment slows elimination, so dosing intervals may increase (eg, 3-4 hours) depending on response.⁷ Cough and insomnia are common AEs, and iloprost may interact with warfarin.^4,7 Transitioning between inhaled iloprost and inhaled treprostinil appears safe and well tolerated.² Treprostinil increases quality of life and improves pulmonary function, with a 68% survival rate at 4 years.^2,4 It is available as an infusion, inhalation, or oral tablet.⁴ A half-life of about 4 hours reduces the dosing frequency.^4,11

Parenteral treprostinil (Remodulin) is given subcutaneously (SC) or intravenously (IV) with a pump.² At room temperature, SC fluid is stable for 72 hours and the IV fluid for 48 hours.² Dosing is started at 1.25 ng/kg/min (IV) or 2.5 ng/kg/min (SC). The average long-term doses are 26 and 42 ng/kg/min, respectively.² Pump/tubing problems (30%), and edema are common AEs.² Local pain and inflammation (SC infusion site pain 85%; not a problem with IV) is doselimiting or leads to discontinuation.^2,4 Use of the same site for 4 or more weeks reduces pain peaks brought on by injection site changes.² Bloodstream infections are less frequent with treprostinil than with epoprostenol (0.36 vs 0.12 infections/1000 treatment days).²

Inhaled treprostinil (Tyvaso) is dosed 4 times a day, at least 4 hours apart.² Dosing starts at 18 mcg (3 breaths/dose); full dose is 54 mcg (9 breaths/dose).² Cough is very common (54%), as is dizziness and throat irritation.² Triple therapy with sildenafil, bosentan, and inhaled treprostinil is associated with a 91% survival rate at 24 months.²

Oral treprostinil (Orenitram) is a sustained- release (2 times/day) tablet.² Oral bioavailability is low (17%). It is dosed with food to increase area under the concentration time curve, C_max, and T_max. Dosing starts at 0.25 mg, increasing to an average of 3.4 mg. Consider recommending 0.25 mg every 8 hours for tolerability, which limits the maximum oral dose. Severe hepatic impairment is a contraindication due to hepatic metabolism of the oral tablet and because the tablet shell does not dissolve. Use with caution in patients with diverticulitis because the tablet may lodge in the diverticulum.²

Endothelin Receptor Antagonists

ERAs mediate vasoconstriction, fibrosis, proliferation, inflammation, vascular hypertrophy, and organ damage.⁸ They counteract endothelin-mediated vasoconstriction and decrease smooth muscle proliferation and remodeling. Endothelin and its receptors are overactive in PAH, however,⁴ which signals poor prognosis.⁹

Bosentan (Tracleer) is an oral medication that improves exercise capacity and functional status, delays clinical worsening, and maintains safety and efficacy up to 5 years.^3,4,10 It is only available through a restricted access program due to its hepatotoxicity and teratogenicity risk; monthly monitoring is mandatory; pregnancy is contraindicated.^4,10 Abnormal liver function tests occur in about 17% of patients, and most events resolve with discontinuation.^3,4 Dosing starts at 62.5 mg twice daily, with or without food, increasing to 125 mg twice daily after 1 month.^4,10 About 30% will need concomitant PAH medications (sildenafil, tadalafil, or prostanoids).³

Ambrisentan (Letairis) is an oral, highly selective ERA that decreases pulmonary arterial pressure, improves lung function and hemodynamics, delays time to clinical worsening, and has a dose-dependent increase in exercise tolerance.^4,9 AEs include peripheral edema, headache, and dose-dependent nasal congestion, but ambrisentan is well tolerated long term.⁹ Dosing starts at 5 mg daily, increasing to 10 mg daily if tolerated; monitor monthly for increased liver function and bilirubin.^4,9 Hemoglobin and hematocrit reductions are possible: recommend baseline levels and periodic monitoring.⁹ Pregnancy is contraindicated.⁹

Macitentan (Opsumit) is an extendedrelease tablet (set dosing: 10 mg once daily) and has a high affinity for, and prolonged binding at, endothelin receptors.¹ It is the first ERA with significantly decreased morbidity and mortality. The drug also causes dose-dependent decreases in mean arterial pressure, but does not affect heart rate or QTc, even at triple the approved dose. It has a black box warning regarding reproductive effects and hemoglobin decreases. Because of possible liver injury, it is not recommended for use in patients with severe hepatic impairment. Macitentan does not interact with warfarin or cyclosporine, it increases sildenafil exposure; ketoconazole doubles to triples macitentan exposure (but is still well tolerated); rifampin decreases macitentan concentrations 4-fold. Pharmacokinetics are not affected by age, sex, meals, ethnicity, or hepatic or renal impairment.¹

Treatment Recommendations

Currently, the preferred treatments for mild (WHO class II) PAH include phosphodiesterase inhibitors (sildenafil and tadalafil), riociguat, and ERAs (bosentan, ambrisentan, and macitentan).² Moderate to severe PAH (WHO classes III and IV) usually require prostacyclin analogs (epoprostenol, iloprost, and treprostinil), which improve mortality, clinical worsening, exercise capacity, and hemodynamics.² Combination therapy with medications with different mechanisms of action is an option; however, studies to date have shown limited improvement in efficacy with combinations tried.⁴ Several more therapeutic approaches are still under study for PAH.⁴ Nonpharmacologic treatments include balloon septostomy or lung transplantation (the treatment of choice when pharmacologic agents are insufficient).^4,9

Debra Freiheit has been a practicing pharmacist and human services professional for more than 25 years. Specializing in medical information, she has compiled a broad spectrum of experience obtained through research for companies including Cerner and PPD Inc. With an emphasis on clear and concise information transfer, Debra has built a career communicating data with medical professionals and patients. Education and knowledge have been the motivation of a rich career of caregiving through research. Debra’s current project involves the creation of a multinational database of drug information.

References

• Sidharta PN, Treiber A, Dingemanse J. Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015;54(5):457-471. doi: 10.1007/s40262-015-0255-5.
• LeVarge BL. Prostanoid therapies in the management of pulmonary arterial hypertension. Ther Clin Risk Manag. 2015;11:535-547. doi: 10.2147/TCRM.S75122.
• Simonneau G, Galie N, Jansa P, et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol. 2014;172(2):332-339. doi: 10.1016/j.ijcard.2013.12.179.
• Goudie AR, Lipworth BJ, Hopkinson PJ, Wei L, Struthers AD. Tadalafil in patients with chronic obstructive pulmonary disease: a randomized, double-blind, parallel-group, placebo controlled trial. Lancet Respir Med. 2014;2(4):293-300. doi: 10.1016/S2213-2600(14)70013-X.
• Veletri [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2012.
• Chin KM, Badesch DB, Robbins IM, et al Two formulations of epoprostenol sodium in the treatment of pulmonary arterial hypertension: EPITOME-1 (epoprostenol for injection in pulmonary arterial hypertension), a phase IV, open-label, randomized study. Am Heart J. 2014:167(2);218-225.e1. doi: 10.1016/j.ahj.2013.08.008.
• Ventavis [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2013.
• Opsumit [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2015.
• Croxtall JD, Keam SJ. Ambrisentan. Drugs. 2008;68(15):2195-2204.
• Tracleer [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2012.
• Remodulin [package insert]. Research Triangle Park, NC . United Therapeutics Corp; 2014.