Kevin Laliberte

Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C Study): A Randomized Controlled Trial

BACKGROUND Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. METHODS A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. RESULTS Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). CONCLUSIONS The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin®) administered by the intravenous and subcutaneous route to normal volunteers

Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (IV/SC) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8–96.1%) and 106% (99.4–113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.

Original ResearchPulmonary Vascular DiseaseFeaturedOral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C Study): A Randomized Controlled Trial

BACKGROUND Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. METHODS A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. RESULTS Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). CONCLUSIONS The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension: A Randomized Controlled Trial

Background— Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. Methods and Results— Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). Conclusions— Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403.

Pharmacokinetics of oral treprostinil sustained release tablets during chronic administration to patients with pulmonary arterial hypertension.

Abstract: Pulmonary arterial hypertension (PAH) is a progressive vascular disease that ultimately leads to right ventricular failure and death. Treprostinil diolamine is an oral prostacyclin analogue; sustained release tablets of oral treprostinil are currently being evaluated for efficacy and safety as a potential therapy in patients with PAH. Previous attempts at developing an oral prostanoid have been limited by rapid absorption and short plasma half-life; thus, the aim of this study was to characterize the pharmacokinetic profile of treprostinil diolamine in PAH patients after chronic dosing. The study enrolled 74 PAH patients who had been taking treprostinil diolamine for a minimum of 4 weeks (range: 0.5–16 mg). We collected plasma samples over 12 hours and estimated pharmacokinetic parameters using noncompartmental methods. Seventy patients had complete data. After chronic twice-daily oral dosing of treprostinil diolamine, mean area under the curve (AUC0-12) of treprostinil increased from 5244 to 20,4086 pg·hr−1·mL−1 and mean maximum observed plasma concentration (Cmax) increased from 1383 to 33588 pg/mL. The apparent clearance (CL/F) was similar across all doses, indicating a linear dose–exposure relationship after twice-daily dosing. We conclude that twice-daily oral treprostinil provides sustained and proportional treprostinil concentrations over a wide range of doses during chronic administration to PAH patients.

Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers.

Treprostinil diethanolamine is an oral prostacyclin analog currently being evaluated for the treatment of pulmonary arterial hypertension (PAH). Treprostinil is metabolized primarily by cytochrome P450 (CYP) 2C8 with minor contribution from CYP2C9. It is expected that oral treprostinil will be administered with bosentan, approved for the treatment of PAH and known to induce CYP2C9 and 3A4. This study evaluated whether a drug interaction exists between oral treprostinil, bosentan, and its active metabolite Ro 48–5033 during co‐administration. Twenty‐four participants were randomized in a 3‐way crossover study to oral treprostinil 1 mg twice daily, bosentan 125 mg twice daily, and oral treprostinil 1 mg twice daily and bosentan 125 mg twice daily. Treprostinil geometric mean ratios (GMRs) (90% confidence interval [CIs]) for steady‐state AUC0–12 and Cmax (combination/treprostinil) were 0.92 (0.83, 1.03) and 0.96 (0.83, 1.11), respectively, whereas bosentan GMRs (combination/bosentan) were 1.02 (0.95, 1.10) and 1.04 (0.94, 1.15), respectively, and Ro 48–5033 GMRs were 0.99 (0.93, 1.06) and 1.03 (0.94, 1.13). In conclusion, because the GMR and 90% CI are within the equivalence interval of 0.8 to 1.25, co‐administration of oral treprostinil and bosentan did not result in a pharmacokinetic interaction for either agent.

Transition from parenteral to oral treprostinil in pulmonary arterial hypertension

BACKGROUND Parenteral prostanoids are effective treatment for pulmonary arterial hypertension, but long-term pump infusion systems have significant delivery-related safety and convenience limitations. METHODS Subjects with a favorable risk profile transitioned from parenteral to oral treprostinil using a protocol-driven titration during 5 days of inpatient observation. Baseline and Week 24 assessments included 6-minute walk distance, echocardiogram, right heart catheterization, pharmacokinetics, treatment satisfaction and quality of life. Thirty-three subjects (76% female, mean age 50 years) enrolled; 85% were using subcutaneous treprostinil with a median dose of 57 (range 25 to 111) ng/kg/min. Participants were using background, approved non-prostanoid therapy, including 9 on 2 oral therapies; baseline right atrial pressure and cardiac output were in the normal range. All 33 subjects transitioned to oral treprostinil therapy within 4 weeks, but 2 transitioned back to parenteral drug before Week 24. At Week 24, subjects were taking a median total daily dose of 44 (15 to 75) mg, with 25 of 31 using a 3-times-daily regimen at 7- to 9-hour intervals. RESULTS The 6-minute walk distance was preserved (median +17 m [-98 to 95 m]) at its baseline of 446 m. Hemodynamic variables, including pulmonary vascular resistance, were similar at Week 24 except for mixed venous saturation, which dropped from a median of 71% to 68% (p < 0.001). Overall quality of life and treatment satisfaction measures did not change; however, mood-related symptom and treatment convenience subscores improved. Common adverse effects included headache, nausea, flushing and diarrhea. CONCLUSIONS Lower risk patients managed on parenteral treprostinil may be candidates for transition to a more convenient, oral form of the drug.

An evaluation of the pharmacokinetics of treprostinil diolamine in subjects with hepatic impairment.

Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue under evaluation for the treatment for pulmonary arterial hypertension (PAH). This study assessed the pharmacokinetics (PK) and safety of treprostinil following oral administration of a single sustained‐release 1 mg dose in subjects with hepatic impairment.

Pharmacokinetics of 3 times a day dosing of oral treprostinil in healthy volunteers.

Background: Treprostinil diolamine (oral treprostinil) is an orally available prostacyclin analog that was developed for the treatment of pulmonary arterial hypertension. This study aimed to evaluate the pharmacokinetics (PK), safety, and tolerability of 3 times daily (TID) dosing of oral treprostinil. Methods: This was a 9-day, open-label, single-center study in which 19 healthy subjects received 0.5 mg oral treprostinil TID for 7 days. On the morning of day 1, subjects received a single 0.5 mg dose and on days 2–7, subjects received 3 doses of 0.5 mg oral treprostinil with a meal (at approximately 8 AM, 2 PM, and 8 PM). On the morning of day 8, subjects received a final 0.5 mg dose. Intensive 24-hour PK sampling occurred after the AM doses on days 1, 7, and 8. Additional trough plasma samples were collected before the morning and evening doses on days 4, 5, and 6. Results: Nineteen subjects (9 men, 10 women) with a mean age of 35.2 years (range, 20–54 years) were enrolled. The majority of subjects were white (n = 17). The mean (% CVb) Cmax was 0.538 (37%), 0.714 (51%), and 0.559 (45%) ng/mL on days 1, 7, and 8, respectively. After a single dose on day 1 (first dose) and day 8 (last dose), mean (CVb%) AUC0–24 was 2.45 (26%) and 2.96 (28%) h·ng·mL−1, respectively. The mean (% CVb) steady-state AUC0–24 after TID regimen (on day 7) was 6.53 (34%) h·ng·mL−1, which was not significantly different from mean AUC0–∞ (7.39 h·ng·mL−1) on day 1 adjusted for 3 doses. Mean apparent t1/2 was similar on days 1, 7, and 8 (1.1–1.4 hours). Trough concentrations of treprostinil were comparable across study days ranging from 0.046 to 0.053 ng/mL before the AM dose and from 0.27 to 0.39 ng/mL before the evening dose. Steady state was achieved within 2 days of TID dosing. Treprostinil PK after TID dosing of oral treprostinil follows linear kinetics and can be predicted based on PK data after a single dose. Sixteen adverse events occurred in 7 subjects and included prostacyclin related adverse events such as headache, diarrhea, and jaw pain. Conclusions: Three times daily dosing of 0.5 mg oral treprostinil for 7 days was well tolerated in healthy subjects and provided sustained plasma exposure throughout the day at steady state without drug accumulation. This study provides data to support further evaluation of TID dosing regimen of oral treprostinil.

Pharmacokinetics of treprostinil diolamine in subjects with end-stage renal disease on or off dialysis.

Abstract: Treprostinil diolamine sustained release (UT-15C SR) is being evaluated as an oral therapy for pulmonary arterial hypertension. This study evaluated the pharmacokinetics (PKs) of treprostinil following administration of UT-15C SR in subjects with end-stage renal disease (ESRD) compared with healthy subjects with normal renal function (NRF) and the effect of hemodialysis on the PK parameters of treprostinil. Eight ESRD subjects (requiring dialysis, mean creatinine clearance = 11.5 mL/min) received 2 single doses of 1 mg of UT-15C SR (separated by 2 weeks), with the first dose given immediately after dialysis and the second given 4 hours before the start of dialysis. Eight NRF subjects received a single dose of 1 mg of UT-15C SR. The median Cmax, AUC0–inf, and t1/2 of treprostinil were 680 pg/mL, 3240 hours⋅pg/mL, and 2.35 hours, respectively, in ESRD subjects dosed after dialysis and were 551 pg/mL, 3152 hours⋅pg/mL, and 2.05 hours, respectively, in ESRD subjects dosed before dialysis. In comparison, corresponding values were 730 pg/mL, 3726 hours⋅pg/mL, and 3.54 hours, respectively, in NRF subjects. UT-15C SR of 1 mg was well tolerated by NRF and ESRD subjects. The most frequent adverse event was headache and nausea. There was no substantial difference in treprostinil PKs between ESRD and NRF subjects following administration of UT-15C SR tablets. Hemodialysis did not have clinically important effect on treprostinil PK in ESRD subjects.