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Treprostinil
Systematic (IUPAC) name
(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 monosodium salt
Identifiers
CAS number 289480-64-4
ATC code B01AC21
PubChem 6918140
Chemical data
Formula C 23H33NaO5  
Mol. mass relative molecular weight is 412.49 g/mol.
Pharmacokinetic data
Bioavailability approximately 100%
Metabolism Treprostinil is substantially metabolized by the liver, but the involved enzymes are not currently known. Five metabolites (HU1 through HU5) have been described thus far. Based on the results of in vitro human hepatic cytochrome P450 studies, Remodulin does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether Remodulin induces these enzymes has not been studied.
Half life 4 hours
Excretion Urine (79 % of administered dose is excreted in the urine as 4% unchanged drug and 64% as identified metabolites); feces (13%)
Therapeutic considerations
Pregnancy cat. B
Legal status  ?
Routes Subcutaneous or intravenous infusion

Treprostinil is a synthetic analogue of prostacyclin (PGI2).

Contents

History

During the 1960s a U.K. research team, headed by Professor John Vane, who was later knighted for his contribution to science, began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Sir John discovered that aspirin and other oral anti-inflammatory drugs worked by inhibiting the synthesis of prostaglandins. This critical finding opened the door to a broader understanding of the role of prostaglandins in the body.

Sir John and a team from the Wellcome Foundation, had identified a lipid mediator they called “PG-X,” which inhibited platelet aggregation. PG-X, which later would become known as prostacyclin, was 30 times more potent than any other known anti-aggregatory agent.

By 1976, Sir John and fellow researcher Salvador Moncada published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthesized molecule, which was given the name epoprostenol. But like native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications.

To overcome this challenge, the research team that discovered prostacyclin was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogues.

Through innovative work done by researcher Lucy Clapp, treprostinil has demonstrated a unique effect on PPAR gamma, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs , another mechanism that contributes to the anti-growth benefits of the prostacyclin class.

Uses and Indications

Pulmonary Arterial Hypertension In Patients With NYHA Class II-IV Symptoms [1] Remodulin is indicated for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms [see CLINICAL STUDIES (14.1)] to diminish symptoms associated with exercise. It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted.

Pulmonary Arterial Hypertension In Patients Requiring Transition From Flolan In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol sodium), Remodulin is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition.

Reference: [1]

Pharmacokinetic Data

The pharmacokinetics of continuous subcutaneous Remodulin are linear over the dose range of 1.25 to 125 ng/kg/min (corresponding to plasma concentrations of about 15 pg/mL to 18,250 pg/m) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 125 ng/kg/min has not been studied.

Mechanisms of Action

File:Trep4.jpg

Clinical Pharmacology

The major effects of treprostinil are vasodilation of arteries in the pulmonary (lung) and body. Treprostinil also inhibits platelet aggregation.

Dosage and Administration

Remodulin may be administered as a continuous subcutaneous infusion or continuous intravenous infusion via a small infusion pump that the patient must wear at all times. Treprostinil is preferentially given subcutaneously by continuous infusion using an infusion set, but may be given intravenously via a central venous catheter if the patient is unable to tolerate subcutaneous administration because of severe site pain or reaction.

Remodulin is supplied in 20 mL vials, containing treprostinil in concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL, and 10 mg/mL. Treprostinil can be administered subcutaneously as supplied. It must be diluted for intravenous infusion with either sterile water or a 0.9% sodium chloride solution prior to administration.

The infusion rate is normally initiated at 1.25 ng/kg/min for new patients, but may be reduced to 0.625 ng/kg/min if the normal rate provokes unwanted side effects in the patient. The infusion rate of treprostinil should be increased no more than 1.25 ng/kg/min per week for the first month, then 2.5 ng/kg/min per week for the remaining duration of infusion. The infusion rate should ideally be high enough to improve symptoms of pulmonary hypertension, while minimizing unpleasant side effects (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction). Dosage adjustments may be undertaken more often if tolerated. There is little experience with doses >40 ng/kg/min. Abrupt cessation of infusion should be avoided. Restarting a Remodulin infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of Remodulin to be re-titrated.

In patients with mild or moderate liver dysfunction, the initial dose of Remodulin should be decreased to 0.625 ng/kg/min ideal body weight and should be increased cautiously. Remodulin has not been studied in patients with severe liver dysfunction.

No studies have been performed in patients with kidney dysfunction. No specific advice about dosing in patients with renal impairment can be given.

The oral form of treprostinil is currently undergoing clinical trials and the inhaled form and data is being reviewed by the FDA.

Important Safety Information

Precautions:

  • Because of treprostinil's inhibiting effect on platelet aggregation, there is an increased risk of bleeding, especially among patients who are also taking anticoagulants.
  • It is not known whether treprostinil is excreted in breast milk. Caution is advised when administering this medication to nursing women.

Common side effects:


Warnings:

  • Abrupt interruption of the treprostinil infusion can lead to worsening of pulmonary hypertension symptoms, and should be avoided.

References

1. ^ Remodulin Full Prescribing Information US Patent No. 5,153,222 ©Copyright 2008 United Therapeutics Corp. All rights reserved.

2. ^ UT_OpinVEvid_FEB09v.1

3. ^ Cost-minimization analysis of treprostinil vs. epoprostenol as an alternate to oral therapy nonresponders for the treatment of pulmonary arterial hypertension

L. Narine a,b, L. K. Hague c, J. H. Walker d,e, C. Vicente d,*, R. Schilz f, O. Desjardins d, T. R. Einarson d,g and M. Iskedjian a,d

a PharmIdeas USA Inc., Charlotte, NC, USA

b University of North Carolina at Charlotte, College of Health and Human Services, Charlotte, NC, USA

c University Hospitals of Cleveland, Cleveland, OH, USA

d PharmIdeas Research & Consulting Inc., Oakville, ON, Canada

e Brock University, Faculty of Business, St. Catharines, ON, Canada

f Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA

g University of Toronto, Faculty of Pharmacy, Toronto, ON, Canada








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