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Orenitram

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Orenitram

CLINICAL PHARMACOLOGY

Mechanism Of Action

The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation, and inhibition of smooth muscle cell proliferation.

Pharmacodynamics

In a clinical trial of 240 healthy adult volunteers, single doses of inhaled treprostinil 54 μg (the target clinical dose) and 84 μg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by approximately 10 msec. The QTc effect dissipated rapidly as the concentration of treprostinil decreased. Orenitram has not been evaluated in a thorough QTc study.

Pharmacokinetics

In patients with PAH, pharmacokinetics of treprostinil is dose-proportional for systemic exposure (AUC0-t) over the dose range of 0.5 and 15 mg BID. Upon repeat administration with a BID regimen, the accumulation in the systemic exposures to treprostinil is minimal and results in a peak-to-trough ratio of approximately 7. However, a TID regimen will reduce the peak-to-trough fluctuations to approximately 2.5 for the same total daily dose.

Absorption

The absolute oral bioavailability of Orenitram is approximately 17%. Maximum treprostinil concentrations occur between approximately 4 and 6 hours following Orenitram administration.

The absorption of Orenitram is affected by food. The AUCinf of treprostinil was increased by 49% and the Cmax was increased by an average of 13% when Orenitram was administered following a high-fat, high-calorie meal compared to fasting conditions in healthy volunteers. The relative bioavailability of treprostinil following oral administration of Orenitram 1 mg is not significantly altered by meal types ranging from 250 to 500 calories in healthy volunteers.

Distribution

The treprostinil component of Orenitram is highly bound to human plasma proteins, approximately 96% over a treprostinil concentration range of 0.01-10 μg/mL.

Metabolism and Excretion

In a study conducted in healthy volunteers using [14C] treprostinil, treprostinil was extensively metabolized on the side chain of the molecule via oxidation, oxidative cleavage, dehydration, and glucuronic acid conjugation. Treprostinil is primarily metabolized by CYP2C8 and to a lesser extent by CYP2C9. No new metabolites are found upon oral administration compared to parenteral administration of treprostinil. Only 1.13% and 0.19% is excreted as unchanged parent drug in the feces and urine, respectively. Based on in vitro studies treprostinil does not inhibit or induce major CYP enzymes [see DRUG INTERACTIONS].

Special Populations

Hepatic Impairment

In subjects with mild (n=8) hepatic impairment, administration of a single 1 mg dose of Orenitram resulted in a mean Cmax and an AUC0-inf that were 1.6-and 2.1-fold, respectively values seen in healthy subjects. With moderate impairment (n=8), the corresponding ratios were 4.0-and 4.8-fold, and with severe impairment (n=6), they were 4.8-and 7.6-fold [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and Use in Specific Populations].

Renal Impairment

In patients with severe renal impairment requiring dialysis (n=8), administration of a single 1 mg dose of Orenitram pre-and post-dialysis resulted in an AUC 0-inf that was not significantly altered compared to healthy subjects.

Drug Interactions

Results of drug interaction studies are shown in Figure 1. Only for the strong CYP2C8 inhibitor does the interaction affect dosing.

Figure 1: Impact of Co-Administered Drugs on the Systemic Exposure of Treprostinil 1 mg Compared to Orenitram Administered Alone

Impact of Co-Administered Drugs on the Systemic Exposure of Treprostinil 1 mg Compared to Orenitram Administered Alone - Illustration

Warfarin

A drug interaction study was carried out with Remodulin co-administered with warfarin (25 mg/day) in healthy volunteers. There was no clinically significant effect of either medication on the pharmacokinetics of treprostinil. Additionally, treprostinil did not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R-and S-warfarin and the international normalized ratio (INR) in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.

Clinical Studies

Clinical Trials In Pulmonary Arterial Hypertension (PAH)

Three multi-center, randomized, double-blind studies were conducted and compared Orenitram to placebo in a total of 349 (Study 1), 350 (Study 2), and 310 (Study 3) patients with PAH.

Study 1 (Effect Seen With No Background Vasodilator)

Study 1 was a 12-week, randomized (2:1 Orenitram to placebo), double-blind, placebo-controlled, international efficacy and safety study of Orenitram in patients with WHO Group 1 PAH not currently receiving PAH therapy. The primary efficacy endpoint was placebo-corrected change in six-minute walk distance (6MWD) from Baseline to Week 12. Study drug dose was titrated to a maximum of 12 mg BID based on clinical response and study drug tolerability. Study 1 enrolled 349 patients (overall analysis population) who were not receiving any PAH medication. At the beginning of the study, subjects were dosed with only the 1 mg tablets with 0.5 and 0.25 mg tablets introduced at sequentially later dates during the study. The primary analysis population consisted of the 228 patients who had access to the 0.25 mg tablet at the time of randomization. Patients were administered Orenitram or placebo twice daily, with the doses titrated to effect over the course of the 12-week trial. Patients were in W HO functional class II (~33%) and class III (~66%) with either idiopathic or heritable PAH (~75%), collagen vascular disease associated PAH (~19%), or PAH associated with HIV (1%) or congenital heart defect (5%) or other conditions (~6%). The patients' mean baseline 6MWD was approximately 330 meters. In the primary analysis population, 17% of patients discontinued Orenitram compared to 14% of patients on placebo.

The primary efficacy endpoint of the trial was the change in 6MWD at 12 weeks for the primary analysis population. Analysis of Study 1 results demonstrated that those patients receiving Orenitram compared to patients receiving placebo improved their median 6MWD by approximately +23 meters (Hodges-Lehmann estimate; p=0.013, non-parametric analysis of covariance in accordance with the pre-specified statistical analysis plan) as compared to patients receiving placebo as demonstrated in (Figure 2). The within group median change from baseline was +25 meters for Orenitram and -5 meters for placebo at week 12 (N=228). Mean dose (±SD) in the Orenitram group was 2.3 ± 1.3, 3.2 ± 1.9, and 3.4 ± 1.9 mg BID at Weeks 4, 8, and 12, respectively. The distribution of the 6MWD change from baseline at W eek 12 was also plotted across the range of observed values (Figure 3).

Figure 2: Hodges-Lehmann Estimate of Treatment Effect by Visit for the Primary Analysis Population (Study 1)

Hodges-Lehmann Estimate of Treatment Effect by Visit for the Primary Analysis Population - Illustration

Figure 3: Plot of the Distribution of Peak 6MWD Changes at Week 12 for the Primary Analysis Population (Study 1)

Plot of the Distribution of Peak 6MWD Changes at Week 12 for the Primary Analysis Population - Illustration

The placebo-corrected median treatment effect on 6MWD was estimated (using the Hodges Lehmann estimator) within various subpopulations defined by age, gender, disease etiology, and baseline 6MWD (Figure 4).

Figure 4: Placebo Corrected Median Treatment Effect (Hodges-Lehmann estimate with 95% CI) on 6MWD Change from Baseline at Week 12 for Various Subgroups in the Primary Analysis Population (Study 1)

Placebo Corrected Median Treatment Effect - Illustration

Studies 2 and 3 (No Effect On A Background Of Era, Pde5 Inhibitor, Or Both)

Studies 2 (N=350) and 3 (N=310) were 16-week, randomized, double-blind, placebo-controlled, international efficacy and safety studies of Orenitram in patients with WHO Group 1 PAH. The primary efficacy endpoint was placebo-corrected change in 6MWD from Baseline to Week 16. Patients were in WHO functional class II (~23%) and class III (~77%) with either idiopathic or heritable PAH (~66%), collagen vascular disease associated PAH (~29%), or PAH associated with HIV (1%) or congenital heart defect (4%). The patients' mean baseline 6MWD was approximately 340 meters. Approximately 40% were receiving both an ERA and a PDE5 inhibitor. The results did not demonstrate a benefit in exercise testing with median 6MWD at Week 16 (11 meters [Hodges-Lehmann estimate; p=0.072] and 10 meters [Hodges-Lehmann estimate; p=0.089], respectively).

Long-Term Treatment of Pulmonary Hypertension

Patients (N=824) from the placebo-controlled studies entered a long-term, uncontrolled, open-label extension study. The average exposure to Orenitram was approximately 2 years with a maximum exposure of approximately 6 years. The dose of Orenitram continued to increase over time with doses (mean ± SD) of 3.6 ± 2.7, 4.2 ± 3.1, and 5 ± 3.7 mg BID at 6 (n=649), 12 (n=433), and 24 months (n=238), respectively. Reasons for discontinuation from the study included adverse event (16%), progression of disease (15%), death (13%), and withdrawn consent (7%). In the 522 subjects that completed the 12-month efficacy assessment, their mean 6MWD improved by 24 meters compared to baseline (30 meters in monotherapy patients and 20 meters when Orenitram was used in combination with an ERA and/or a PDE-5 inhibitor). Of the patients that remained in the study, overall survival was 92%, 87%, and 82% at the end of 1, 2, and 3­years, respectively, with progression-free survival (progression defined as death, discontinuation or addition of a PAH therapy) of 74%, 61%, and 47%. Without a control group, these data must be interpreted cautiously.

Last reviewed on RxList: 10/20/2014
This monograph has been modified to include the generic and brand name in many instances.

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