| Indication |
For use as a continuous subcutaneous infusion or intravenous
infusion (for those not able to tolerate a subcutaneous infusion) for
the treatment of pulmonary arterial hypertension in patients with NYHA
Class II-IV symptoms to diminish symptoms associated with exercise. |
| Pharmacodynamics |
Pulmonary arterial hypertension (PAH) is a disease in which
blood pressure is abnormally high in the arteries between the heart and
lungs. PAH is characterized by symptoms of shortness of breath during
physical exertion. The condition can ultimately lead to heart failure.
Treprostinil is a potent oral antiplatelet agent. The major
pharmacologic actions of treprostinil are direct vasodilation of
pulmonary and systemic arterial vascular beds and inhibition of platelet
aggregation. In animals, the vasodilatory effects reduce right and left
ventricular afterload and increase cardiac output and stroke volume.
Other studies have shown that treprostinil causes a dose-related
negative inotropic and lusitropic effect. No major effects on cardiac
conduction have been observed. |
| Mechanism of action |
The major pharmacological actions of treprostinil are direct
vasodilation of pulmonary and systemic arterial vascular beds and
inhibition of platelet aggregation. In addition to treprostinil's direct
vasodilatory effects, it also inhibits inflammatory cytokine. As a
synthetic analogue of prostacyclin, it binds to the prostacyclin
receptor, which subsequently induces the aforementioned downstream
effects. |
| Absorption |
Relatively rapid and complete after subcutaneous infusion, with an
absolute bioavailability approximately 100%. In patients with mild
(n=4) or moderate (n=5) hepatic insufficiency and portopulmonary
hypertension following a subcutaneous dose of 10 ng per kg of body
weight per min for 150 mins the AUC 0-∞ was increased 3-fold and 5-fold
respectively. |
| Volume of distribution |
|
| Protein binding |
Human plasma protein binding is approximately 91% in in vitro concentrations ranging from 330 to 10,000 ยต/L. |
| Metabolism |
Substantially metabolized by the liver, but the precise enzymes
responsible are unknown. Five metabolites have been described (HU1
through HU5) however, the biological activity and metabolic fate of
these are unknown. The chemical structure of HU1 is unknown. The
metabolite HU5 is the glucuronide conjugate of treprostinil. The other
metabolites are formed by oxidation of the 3-hydroxyoctyl side chain
(HU2) and subsequent additional oxidation (HU3) or dehydration (HU4).
Study results of in vitro human hepatic cytochrome P450 demonstrates
that treprostinil does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A.
Whether treprostinil induces these enzymes has not been studied. |
| Route of elimination |
Not Available |
| Half life |
Terminal elimination half-life is approximately 2 to 4 hours.
Plasma half-life is 34 and 85 minutes for intravenous and subcutaneous
infusion of the drug, respectively. |
| Clearance |
Not Available |
| Toxicity |
Symptoms of overdose are extensions of its dose-limiting
pharmacologic effects and include flushing, headache, hypotension,
nausea, vomiting, and diarrhea. Most events were self-limiting and
resolved with reduction or withholding of treprostinil. |
