Treprostinil (marketed under the trade names Remodulin, a sodium salt of treprostinil for infusion and Tyvaso for inhalation, both manufactured and marketed by United Therapeutics and chemically known as (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl] oxy]acetic acid) is a synthetic form of the lipid molecule prostacyclin (also called prostaglandin, denoted as PGI2), belonging to the class of eicosanoids. These molecules are potent vasodilators and are used to treat patients with Pulmonary Arterial Hypertension (more specifically those classified to possess classes II to IV symptoms of PAH as demarcated by researchers at the New York Heart Association or NYHA) in order to improve exercising ability and reduce clinical worsening. The drug is an intravenous formulation to be administered subcutaneously or intravenously, also available in the form of tablets and inhalables.
How Treprostinil Works
Being a potent prostacyclin analogue, treprostinil is involved in vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation and clotting. It does so by increasing the amount of cyclic adenosine monophosphate (cAMP), which in turn balances the excess amount of calcium released in the cytosol. When balanced, the calcium ions ensure dephosphorylation of enzymes which are crucial to muscle contraction. This leads to smooth muscle relaxation and vasodilation.
Treprostinil Clinical Trials and Approval
Tyvaso was approved by the FDA in July 2009 following successful results released by United Therapeutics from their landmark clinical trial TRIUMPH, a 12-week, randomized, double-blind, placebo-controlled multi-center study involving around 235 patients. These patients were confirmed to be on either bosentan or sildenafil therapy for a minimum of three months prior to enrolment for this study. The subjects received either placebo or Tyvaso in four daily sessions with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. The primary efficacy endpoint was the improvement in six-minute walk distance (6MWD) relative to baseline at 12 weeks. Positive results ensured the drug’s safety, tolerance and efficacy in patients, which led to its approval by the FDA. (It is to be noted that Remodulin had been approved by the FDA in May 2002, after successful results from clinical trials as well).
Treprostinil Dosage and Indications
Dosage for Tyvaso is ideally recommended to begin with 3 breaths (equivalent to 18 mcg of treprostinil), per treatment session, 4 times daily. If 3 breaths are not tolerated, doses should be reduced to 1 or 2 breaths and subsequently increased to 3 breaths, as per patient tolerance. As the therapy progresses, it is advisable to increase dosage by an additional 3 breaths at approximately 1-2 week intervals, if tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached per treatment session, 4 times daily. In the unwarranted phenomenon of adverse effects, dosage should be continued at the highest tolerated dose. The maximum recommended dosage is 9 breaths per treatment session, 4 times daily.
Remodulin is supplied in concentrations of 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL and 10.0 mg/mL. The standard infusion rate is 1.25 ng/kg/min, but can be reduced in the event where the original dose cannot be tolerated by the patient.
Common adverse effects for treprostinil include cough, headache, nausea, throat irritation, flushing, temporary loss of consciousness or fall in blood pressure, jaw pain, hypotension and edema. Since the drug has anticoagulation properties, those who are already on anticoagulants should consult a specialist before taking treprostinil. Same follows for patients with hepatic or renal insufficiencies. Pregnant women or those planning to conceive should refrain from using the drug unless advised otherwise.