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Subcutaneous treprostinil in pulmonary arterial hypertension: Practical considerations

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Treprostinil, which is available for subcutaneous (SC) and intravenous (IV) administration, has demonstrated efficacy in increasing exercise capacity, reducing signs and symptoms of pulmonary arterial hypertension (PAH), and improving cardiopulmonary hemodynamics in patients with PAH; however, the infusion site pain commonly experienced with SC treprostinil has limited its use. Prospective and observational clinical studies have shown that the dose of SC treprostinil can be escalated at a higher rate than described in early clinical trials to achieve symptom relief, in part because of favorable tolerability of treatment and the apparent dose independence of site pain. In addition, pain management protocols that include non-pharmacologic and pharmacologic (i.e., topical and systemic) approaches provide analgesic relief from infusion site pain. With experience, physicians and patients have recognized that some infusion sites are better than others, and the frequency of site rotation can be reduced to improve tolerability. Dosing to achieve rapid onset of efficacy and proactively managing infusion site pain enhance the likelihood for a patient with PAH to maintain and derive benefit from SC treprostinil therapy.

Section snippets

Clinical profile of SC treprostinil

Subcutaneously administered treprostinil is rapidly and completely absorbed, with 100% bioavailability.18 The pharmacokinetics of SC treprostinil (steady state) were demonstrated to be dose proportional over a range of 2.5 to 15 ng/kg/min in healthy volunteers and 10 to 125 ng/kg/min in patients with PAH (Figure 1).19, 20 Among healthy volunteers administered treprostinil 10 to 15 ng/kg/min, plasma concentration rose rapidly and reached maximum plasma concentration within 2 to 3 hours after

Patient selection

Treatment decisions are based on clinical measures as well as physician and patient preference, financial considerations (insurance/reimbursement) and experience of the PAH center. Treprostinil is indicated for patients with New York Heart Association Functional Class (FC) II to IV symptoms to diminish symptoms associated with exercise and for patients requiring transition from epoprostenol.26 In practice, SC treprostinil is used in newly diagnosed FC III patients and patients who are

Disclosure statement

Editorial assistance was provided under the direction of the authors by MedThink Communications with support from United Therapeutics Corporation.

M.A.M. received a grant from Actelion Pharmaceuticals, Ltd., to study pulmonary rehabilitation in patients with PAH and he is a consultant to Actelion Pharmaceuticals, Ltd., Gilead Sciences, Inc., and United Therapeutics Corporation. S.M. is an employee of United Therapeutics Corporation. R.S. is a consultant to United Therapeutics Corporation and

References (47)

  • L.K. Ashby et al.

    Protocol for reduction of site pain in the administration of treprostinil

    Chest

    (2004)
  • K.M. Chin et al.

    Pulmonary arterial hypertension

    J Am Coll Cardiol

    (2008)
  • J. Hiremath et al.

    Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial

    J Heart Lung Transplant

    (2010)
  • H. Olschewski et al.

    Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension

    Chest

    (2003)
  • R. Voswinckel et al.

    Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies

    J Am Coll Cardiol

    (2006)
  • R.N. Channick et al.

    Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension

    J Am Coll Cardiol

    (2006)
  • R. Voswinckel et al.

    Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension

    Pulm Pharmacol Ther

    (2008)
  • M. Gomberg-Maitland et al.

    Prostacyclin therapies for the treatment of pulmonary arterial hypertension

    Eur Respir J

    (2008)
  • M. Humbert et al.

    Treatment of pulmonary arterial hypertension

    N Engl J Med

    (2004)
  • R.J. Barst et al.

    A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

    N Engl J Med

    (1996)
  • M. Humbert et al.

    Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study

    Eur Respir J

    (1999)
  • M. Gomberg-Maitland et al.

    Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension

    Am J Respir Crit Care Med

    (2005)
  • N. Skoro-Sajer et al.

    A clinical comparison of slow- and rapid-escalation treprostinil dosing regimens in patients with pulmonary hypertension

    Clin Pharmacokinet

    (2008)
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