Skoro-Sajer et al Until in the early 1990s, PAH was a uniformly fatal disease, with a median life expectancy of about 2.5 years. Uncontrolled studies showed that a small proportion of patients responded to high-dose calcium channel blockers, retrospective studies supported the use of anticoagulant therapy, and “conventional treatment” was otherwise limited to life style counseling, diuretics, digitalis, and supplemental oxygen (Naeije and Vachiery 2001). Chronic continuous intravenous prostacyclin (epoprostenol, Flo- lan®) was introduced in the 1980s to bridge patients with idiopathic PAH (IPAH) to transplantation (Higenbottam et al 1993). Epoprostenol was thereafter shown by two randomized controlled trials to improve functional state, exercise capacity, and survival in idiopathic PAH (Barst et al 1996) and to improve functional state and exercise capacity in CTD-PAH (Badesch et al 2000). These trials led to the FDA approval of epoprostenol for New York Heart Association (NYHA) functional classes III and IV patients with IPAH in 1996, with label extension to include CTD-PAH in 2000. Extensive experience of long-term treatment with chronic intravenous epoprostenol has conﬁrmed persistent clinical beneﬁt over years in IPAH (McLaughlin et al 2002; Sitbon et al 2002), CHD-PAH (Rosenzweig et al 1999), portal hypertension-associated PAH (Kuo et al 1997), and HIV-PAH (Nunes et al 2003). Good long-term results of chronic intravenous epoprostenol has led to withdrawal of PAH patients from waiting lists for transplantation (Robbins et al 1998). Intravenous epoprostenol has been reported to help bridging CTEPH patients to thromboendarterectomy (Nagaya et al 2003). Chronic intravenous epoprostenol has been established as the gold standard of PAH therapy. It is recommended as ﬁrst line for NYHA IV patients, and as add-on for patients remaining in NYHA functional class III in spite of correctly dosed ERA, PDE-5 inhibitors, or both (Galie et al 2004; Badesch et al 2007). However, the treatment is not ideal. Because of instability and very short half-life (2–7 min), epoprostenol must be administered as a continuous infusion through a permanently implanted central venous catheter. This exposes the patients to a series of complications includ- ing catheter-related embolism or thrombosis, infections, and delivery system malfunctions resulting in poorly tolerated rapid overdosing or under-dosing. Therefore, more stable prostacyclin derivatives and different routes of administration have been developed. The ﬁrst to be proposed as an alter- native to intravenous epoprostenol has been subcutaneous treprostinil (Simonneau et al 2002). Pharmacology of treprostinil Treprostinil (see Figure 1) is a tricyclic benzindene analogue of prostacyclin, and has as such similar anti-platelet and vasodilatory actions, including acute pulmonary vasodilation (Vachiery and Naeije 2004). This prostanoid is rapidly and completely absorbed after subcutaneous administration with an absolute bioavailability of 100%. Continuous subcutaneous infusion of treprostinil is associated with steady state plasma concentrations after about 10 h with administration rates from 1.25 to 22 ng/kg/min. The metabolism of treprostinil is hepatic, although the enzymes involved are not exactly known. Approximately 79% of the administered dose is excreted in the urine either as unchanged drug (4%) or an identiﬁable metabolite (64%). The safety of treprostinil is favorable, with in particular no reproductive toxicity or teratogenicity. The clearance of treprostinil is decreased up to 80% in patients with hepatic insufﬁciency, requiring therefore cautious dosing in patients with PAH associated with liver disease. There are no studies on the pharmacokinetics of treprostinil in patients with renal insufﬁciency. Treprostinil does not interfere with the metabolism of paracetamol, warfarin, or digoxin (Wade et al 2003, 2004). Treprostinil is chemically stable in either sterile water or 0.9% sodium chloride and 5% dextrose solutions at room temperature, and has a close to neutral pH (Phares et al 2003). Figure 1 Chemical structure of treprostinil sodium (left) and epoprostenol sodium (right). 508 Vascular Health and Risk Management 2008:4(3)