Treprostinil

Information about Treprostinil

Prostacyclin is a small lipid eicosanoid molecule also known as prostaglandin I-2 (PGI-2) that is produced by endothelial cells and acts locally, inhibiting platelet activation and causing vasodilation. Analogs of prostacyclin have been developed as therapies of pulmonary arterial hypertension (PAH).

Liver safety of Treprostinil

Prostacyclin is synthesized in endothelial cells and released in response to local factors such as inflammation and injury. Prostacyclin acts locally on receptors present on endothelial cells and platelets activating adenyl cyclase and thereby increasing intracellular cyclic adenine monophosphate (cAMP), a signaling molecule that activates multiple downstream pathways. In platelets, cAMP inhibits their activation, thus limiting the formation of platelet clots and decreasing hemostasis. In endothelial cells, intracellular cAMP activate pathways to induce smooth muscle relaxation and vasodilation. Prostacyclin is a paracrine signaling molecule, acting locally and with a very short half-life. When used as a drug, it is referred to as epoprostenol which is a potent vasodilator, particularly of the pulmonary vascular bed. Because of its short half-life and relative instability, epoprostenol requires continuous intravenous infusion and special handling. Several analogs of prostacyclin have been produced that have a longer half-life and greater stability, resulting in more favorable pharmacokinetics and bioavailability allowing administration by subcutaneous and oral routes or by inhalation.

List of Treprostinil

Prostacyclin analogs in clinical use in the United States include epoprostenol, iloprost and treprostinil. All three are used to treat pulmonary arterial hypertension (PAH), a severe and progressive disease marked by vasoconstriction and smooth muscle cell proliferation of the pulmonary arterioles. Importantly, PAH is associated with a relative increase in mediators of vasoconstriction (endothelin-1, thromboxane A) and a relative decrease in mediators of vasodilation (prostacyclin, nitric oxide). Modern therapy of PAH often combines antagonists of vasoconstrictors with agonists of the vasodilatory mediators. All three of the vasodilatory prostacyclin analogs require careful and monitored dose adjustments and should be administered only by physicians and health care providers trained and experienced in the management of PAH. None of the prostacyclin analogs have been convincingly linked to instances of clinically significant acute liver injury.

Epoprostenol

Epoprostenol (e" poe pros' ten nol) is the pharmaceutical name for prostacyclin, a naturally occurring metabolite of arachidonic acid that causes pulmonary arterial vasodilation and inhibits platelet activation. Epoprostenol must be given parenterally and has a short half-life (~6 minutes), for which reasons it is administered as a continuous intravenous infusion. In multiple clinical trials in patients with PAH, prolonged epoprostenol infusions led to an increase in exercise capacity (6 minute walk distance), improvement in symptoms and delay in clinical progression in patients with idiopathic and inheritable forms of PAH (WHO Group 1) and connective tissue disease-associated PAH.

FDA approval information for Treprostinil

Epoprostenol was approved for use in the United States in 1995 and remains available generically and under the brand name Flolan. Epoprostenol is provided as a sterile powder in single use vials of 0.5 or 1.5 mg. The typical dose is 2 ng per kg body weight per minute administered via an implanted central venous catheter. The dose can be increased in increments of 1 to 2 ng/kg/min based upon clinical response and tolerance.

Side effects of Treprostinil

Common side effects include dizziness, jaw pain, headache, muscle pain, gastrointestinal upset, nausea and vomiting, effects commonly associated with vasodilatory therapies. Uncommon, but potentially severe adverse events include pulmonary edema, hypotension, syncope, and bleeding. Sudden discontinuation can lead to rebound pulmonary hypertension. Side effects of the intravenous catheter required for administration include local pain, swelling and infection at the site of injection and catheter-associated bacterial infections that can be severe and result in fatality. Epoprostenol has not been associated with serum enzyme elevations above the rate in control subjects and has not been linked to instances of clinically apparent acute liver injury.

Iloprost

Iloprost (eye' loe prost) is a synthetic prostacyclin analog that is more stable and has a longer half-life than epoprostenol and can be given by inhalation. Chronic inhalation therapy using iloprost has been shown to improve symptoms, exercise capacity and pulmonary function in patients with PAH, WHO type 1. Iloprost was approved for use in the United States in 2004 and is usually given in combination with other agents for PAH. Iloprost is available in ampules of 10 or 20 µg/mL under the brand name Ventavis and is administered via a nebulizer in doses of 2.5 to 5.0 µg, 6 to 9 times daily. Because of its short half-life, iloprost must be administered frequently (minimum of 2 hours between doses), a requirement that limits its acceptability. Common side effects include flushing, cough, headache, dizziness, insomnia, palpitations, jaw pain, muscle pain, palpitations, nausea and vomiting. Uncommon, but potentially severe adverse events include hypotension, hemoptysis, pulmonary edema, bronchospasm and pneumonia. Iloprost has not been associated with serum enzyme elevations above the rate in control subjects and has not been linked to instances of clinically apparent acute liver injury.

Treprostinil

Treprostinil (tre pros’ ti nil) is a tricyclic benzidine analog of prostacyclin that can be administered orally, by inhalation, subcutaneously or by intravenous infusion. It has a longer half-life (3 to 4 hours) than epoprostenol and iloprost and is stable at room temperature and neutral pH, making it more convenient to administer when given parenterally. Intravenous and subcutaneous forms of treprostinil have been found to be better accepted than other intravenously administered prostacyclin analogs and to have similar long term efficacy.

FDA approval information for Treprostinil

Treprostinil was initially approved for use in PAH (WHO Group 1) in the United States in 2002 and is available in solution for injection in vials of 1.0, 2.5, 5.0 and 10.0 mg/mL under the brand name Remodulin, the typical dose being 1.25 to 2.5 ng/kg per minute. Treprostinil is also available as a solution for inhalation under the brand name Tyvaso in 2.9 mL ampules with 1.74 mg/ampule, the usual dose being 3 to 9 breaths four times daily. Finally, oral treprostinil tablets of 0.125, 0.25, 1 and 2.5 mg are available under the brand name Orenitram, the initial dose being 0.125 three times daily or 0.25 twice daily, with careful adjustment of dose thereafter based upon tolerance.

Side effects of Treprostinil

Side effects of treprostinil are similar to those of iloprost and epoprostenol and include headache, diarrhea, nausea and vomiting, flushing, dizziness, paresthesia, muscle and jaw pain. Sudden withdrawal of therapy can cause rebound worsening of pulmonary hypertension. Inhalation therapy can cause cough. Chronic intravenous therapy with treprostinil is associated with a high rate of infusion site pain and erythema and with catheter-associated bacterial infections that can be severe and have resulted in death in rare instances. The oral form of treprostinil has limited efficacy and is considered a second line therapy of PAH generally given with other oral agents for PAH or to replace intravenous or subcutaneous treprostinil in patients with poor tolerance of the parenteral therapies.

Liver safety of Treprostinil

Treprostinil therapy has not been associated with serum enzyme elevations above the rate in control subjects and has not been linked to instances of clinically apparent acute liver injury.

Pulmonary Disease Agents

• Chronic Obstructive Pulmonary Disease (COPD) Agents
  • Anticholinergic Agents
    • Ipratropium, Tiotropium, Aclidinium
  • Beta-2 Adrenergic Agonists
    • Albuterol, Formoterol, Salmeterol, Terbutaline
  • Corticosteroids
    • Budesonide, Fluticasone
  • Miscellaneous
    • Roflumilast, Theophylline

• Pulmonary Arterial Hypertension Agents
  

• • Endothelin Receptor Antagonists
    • • Ambrisentan, Bosentan, Macitentan
  • Phosphodiesterase Type 5 (PDE5) Inhibitors
    • Avanafil, Sildenafil, Tadalafil, Vardenafil
  •  Prostacyclin Analogs
    • Epoprostenol, Iloprost, Treprostinil
  •  Miscellaneous
    • Riociguat, Selexipag

• Pulmonary Fibrosis Agents
  • Nintedanib, Pirfenidone

• Dailymed label info on Treprostinil
• FDA Treprostinil

Treprostinil Resources
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