Sustained Plasma Concentrations of Treprostinil Following Chronic Dosing in Patients with Pulmonary Arterial Hypertension (PAH).

Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension

“…Previous pharmacokinetic data suggest that PAH patients treated with this dose of oral treprostinil would exhibit clinically relevant serum treprostinil concentrations similar to those seen with parenteral infusion rates of ≈10 to 30 ng·kg −1 ·min −1 and similar to or greater than those seen with the recommended maintenance dose (54 µg 4 times a day) of inhaled treprostinil. 23,27,28 More than half (52%) of the patients treated with oral treprostinil demonstrated at least a 20-m improvement in 6MWD at week 12, and 34% had an improvement of ≥50 m. These improvements are similar to those observed with the addition of inhaled treprostinil to background ERA or PDE-5I therapy (52% ≥20 m; 31% ≥50 m). 16 Interestingly, the improvements seen in the placebo group in the present study (39% ≥20 m; 23% ≥50 m) were actually greater than those observed for the placebo group in the inhaled treprostinil study (32% ≥20 m; 12% ≥50 m), 16 despite the fact that patients given placebo in the present study were not receiving background therapy.…”

“…In the placebo group, 3 patients (3%) discontinued study drug because of AEs. The overall incidence and severity of AEs was similar for the mITT population, although fewer oral treprostinil patients in the mITT population prematurely discontinued study drug because of AEs (ITT, 23 Values shown as mean (range), n (%), n, or mean±SD. CHD indicates congenital heart disease; CVD, collagen vascular disease; HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; ITT, intent-to-treat; mITT, modified intent-to-treat; PAH, pulmonary arterial hypertension; 6MWD, 6-minute walk distance; and WHO, World Health Organization.…”

“…Exercise capacity was also assessed at week 11. On the basis of prior pharmacokinetic analyses, 23 exercise capacity was assessed at estimated peak (3-6 hours after morning administration [weeks 4, 8, and 12]) and trough (8-13 hours after last dose [week 11]) plasma concentrations of treprostinil. Clinical laboratory parameters were assessed at baseline, week 8, and week 12; 12-lead ECG was conducted at baseline and week 12; and clinical worsening assessment and AEs were recorded throughout the 12-week study period.…”

“…In pharmacokinetic studies involving PAH patients undergoing chronic, open-label therapy, treprostinil diolamine demonstrated a terminal half-life of ≈4.5 hours with a broad and sustained blood concentration for 8 to 10 hours after a single oral dose. 23 Oral treprostinil diolamine is primarily subject to CYP2C8 and, to a lesser extent, CYP2C9 metabolism and demonstrates increased bioavailability with food. 24,25 In PAH patients, an oral treprostinil dose of 3.5 mg BID produced plasma levels between 2 and 8 hours after the dose that were comparable to those seen with parenteral infusion rates of 10 to 30 ng·kg…”

“…23 The first completed study with oral treprostinil (Oral Treprostinil in Combination With an ERA and/or a PDE-5I for the Treatment of PAH [FREEDOM-C]) failed to meet its primary end point. In that 16-week randomized, placebo-controlled study, PAH patients receiving approved background therapy (ERA, PDE-5I, or both) treated with oral treprostinil therapy had a nonsignificant increase in 6-minute walk distance (6MWD) of 11 m (P=0.07).…”