Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients Transitioned from Parenteral or Inhaled Prostacyclins: Case Series and Treatment Protocol

Abstract

Oral treprostinil (TRE) is a prostacylin approved for the management of pulmonary arterial hypertension (PAH). Few data exist to guide the use of oral TRE as a replacement for parenteral or inhaled prostacyclins. Therefore, the purpose of this report was to describe our experience with oral TRE to transition patients from parenteral or inhaled TRE. We describe a case series of patients admitted for a 4-day hospital stay to transition from parenteral or inhaled TRE. Appropriate criteria for transition included stable patients with improved symptoms/functional capacity, patients who could not tolerate intravenous prostacyclin due to infection or subcutaneous prostacyclin due to pain, and patient preference for transition. The dosing protocol for transition is described. A total of 9 patients generally representative of a typical PAH demographic and background medical therapy were included. Patients were initiated at either 0.5 or 1 mg 3 times daily and discharged on a median dose of 8 mg 3 times daily. Our protocol resulted in 6 of 9 patients who successfully transitioned at a median follow-up of 47 weeks. Two patients had to return to their previous prostacyclin therapy based on the presence of clinical worsening and adverse events (n = 1) and adverse events alone (n = 1). Another patient discontinued therapy due to plans for hospice care. Oral TRE may serve an important role in prostacyclin transitions in carefully selected, stable patients who receive background oral therapy for PAH.Keywords: prostacyclin, oral treprostinil, transition, switch, pulmonary hypertension. Parenteral prostacyclins are the mainstay of treatment for patients with advanced symptoms of pulmonary arterial hypertension (PAH) as they have made a significant impact on exercise capacity, symptoms, and hemodynamics.1 However, their use is fraught with complications related to their administration, such as injection-site pain with subcutaneous (SQ) use or line-related bloodstream infections with intravenous (IV) use. 1 Oral treprostinil (TRE) was approved in 2013, although clinical trial evidence demonstrated a modest improvement in 6-minute walk distance (6MWD) when given as monotherapy and no improvement as part of combination therapy. 2-5 These results, however, were likely confounded by subtherapeutic dosing and suboptimal dosing titration that resulted in a high proportion of adverse events (AEs) and premature study discontinuation. [3][4][5] Efforts to improve patient tolerability and reach optimal dosing have resulted in administration requirements and titration schedules that can be relatively complex. 2 Nonetheless, careful attention to dosing and monitoring have generated interest among clinicians and patients in the potential to replace parenteral prostacyclins with oral TRE. However, data to guide such prostacyclin transitions have thus far been limited. 6CASE DESCRIPTION At University of Pittsburgh Medical Center Presbyterian University Hospital, we developed guidelines for use of oral TRE, including suggested parameters...

Pulmonary arterial hypertension: tailoring treatment to risk in the current era

“…Additional data are emerging from clinical practice and there is growing experience with managing this transition in the clinic. Patients receiving parenteral prostanoid therapy may request to switch to an oral drug and limited data from short-term studies on this approach are beginning to emerge [61][62][63][64][65][66][67]. Validation of this approach in RCTs will be required before it can be recommended.…”

Different efficacy of inhaled and oral medications in pulmonary hypertension

“…Jorgensen et al(11) transitioned 6 pediatric patients (7–21 years old) with PAH from inhaled (average dose of 172 mcg/day) to oral treprostinil (average dose of 3.5 mg/day) and of them, 3 experienced side effects (nausea, diarrhea, and loss of appetite) and one had sudden death (unclear if related to the transition or other factors) (11). Coons et al (10) transitioned 2 patients with PAH from inhaled (72 mcg 4 times a day) to oral treprostinil (2.5 mg for one and 4 mg for the other subject, given every 8 hours). Both patients had side effects including headache, jaw pain, diarrhea and flushing.…”

“…Both patients had side effects including headache, jaw pain, diarrhea and flushing. In one subject the dose was increased to 7mg every 6 hours (week 52 from initial transition), while the other patient was later enrolled in hospice (10). Khan et al (12) transitioned 2 PAH patients from inhaled (54 and 72 mcg 4 times a day) to oral treprostinil (3 mg every 8 hours).…”

Positioning Newer Agents: Riociguat, Selexipag, and Oral Treprostinil in the Current Landscape

“…4 Transition from inhaled prostanoids to oral treprostinil has also been reported. 6 Oral treprostinil thus is in the difficult position of having a weak evidence base for its use, yet some practitioners (including the author) have been successful in utilizing it to good effect in some patients, including those on other background therapy. There is the sense that the treprostinil molecule is an effective pulmonary vasodilator, and it is hoped that the ongoing trial will further establish the efficacy and tolerability of oral treprostinil in combination therapy.…”

“…Patients have also been successfully transitioned from inhaled prostanoids to oral treprostinil, thereby avoiding the inconvenience of qid inhalation therapy. 5,6 Riociguat is the first-in-class Food and Drug Administration (FDA)-approved soluble guanylate cyclase (sGC) stimulator, approved for treatment of Group 1 PAH and inoperable or residual Group 4 pulmonary hypertension (PH)-the first drug with adequate evidence in chronic thromboembolic pulmonary hypertension (CTEPH) to achieve labeling for this indication. By directly stimulating sGC, and amplifying the sGC responsiveness to nitric oxide, it drives increased production of cyclic guanosine monophosphate (cGMP), the second messenger that mediates the nitric oxide vasodilatory response.…”