July 30, 2016
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Mechanism Of Action

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


In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed.

Treprostinil produces vasodilation and tachycardia. Single doses of treprostinil up to 84 mcg by inhalation produce modest and short-lasting effects on QTc, but this is apt to be an artifact of the rapidly changing heart rate. Treprostinil administered by the subcutaneous or intravenous routes has the potential to generate concentrations many-fold greater than those generated via the inhaled route; the effect on the QTc interval when treprostinil is administered parenterally has not been established.


The pharmacokinetics of continuous subcutaneous Remodulin are linear over the dose range of 1.25 to 125 ng/kg/min (corresponding to plasma concentrations of about 15 pg/mL to 18,250 pg/mL) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 125 ng/kg/min has not been studied.

Subcutaneous and intravenous administration of Remodulin demonstrated bioequivalence at steady state at a dose of 10 ng/kg/min.


Remodulin is relatively rapidly and completely absorbed after subcutaneous infusion, with an absolute bioavailability approximating 100%. Steady-state concentrations occurred in approximately 10 hours. Concentrations in patients treated with an average dose of 9.3 ng/kg/min were approximately 2,000 pg/mL.


The volume of distribution of the drug in the central compartment is approximately 14L/70 kg ideal body weight. Remodulin at in vitro concentrations ranging from 330-10,000 mcg/L was 91% bound to human plasma protein.

Metabolism and Excretion

Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. In a study conducted in healthy volunteers using [14C] treprostinil, 78.6% and 13.4% of the subcutaneous dose was recovered in the urine and feces, respectively, over 10 days. Only 4% was excreted as unchanged treprostinil in the urine. Five metabolites were detected in the urine, ranging from 10.2% to 15.5% and representing 64.4% of the dose administered. Four of the metabolites are products of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative (treprostinil glucuronide). The identified metabolites do not appear to have activity.

The elimination of treprostinil (following subcutaneous administration) is biphasic, with a terminal elimination half-life of approximately 4 hours using a two compartment model. Systemic clearance is approximately 30 L/hr for a 70 kg person.

Based on in vitro studies treprostinil does not inhibit or induce major CYP enzymes [see DRUG INTERACTIONS].

Special Populations

Hepatic Insufficiency

In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic insufficiency, Remodulin at a subcutaneous dose of 10 ng/kg/min for 150 minutes had a Cmax that was 2-fold and 4-fold, respectively, and an AUC 0- that was 3-fold and 5-fold, respectively, values observed in healthy subjects. Clearance in patients with hepatic insufficiency was reduced by up to 80% compared to healthy adults.

Renal Insufficiency

No studies have been performed in patients with renal insufficiency, so no specific advice about dosing in such patients can be given. Although only 4% of the administered dose is excreted unchanged in the urine, the five identified metabolites are all excreted in the urine.

Clinical Studies

Clinical Trials In Pulmonary Arterial Hypertension (PAH)

Two 12-week, multicenter, randomized, double-blind studies compared continuous subcutaneous infusion of Remodulin to placebo in a total of 470 patients with NYHA Class II (11%), III (81%), or IV (7%) pulmonary arterial hypertension (PAH). PAH was idiopathic/heritable in 58% of patients, associated with connective tissue diseases in 19%, and the result of congenital systemic-topulmonary shunts in 23%. The mean age was 45 (range 9 to 75 years). About 81% were female and 84% were Caucasian. Pulmonary hypertension had been diagnosed for a mean of 3.8 years. The primary endpoint of the studies was change in 6-minute walking distance, a standardmeasure of exercise capacity. There were many assessments of symptoms related to heart failure, but local discomfort and pain associated with Remodulin may have substantially unblended those assessments. The 6-minute walking distance and an associated subjective measurement of shortness of breath during the walk (Borg dyspnea score) were administered by a person not participating in other aspects of the study. Remodulin was administered as a subcutaneous infusion, described in Section 2, DOSAGE AND ADMINISTRATION, and the dose averaged 9.3 ng/kg/min at Week 12. Few subjects received doses > 40 ng/kg/min. Background therapy, determined by the investigators, could include anticoagulants, oral vasodilators, diuretics, digoxin, and oxygen but not an endothelin receptor antagonist or epoprostenol. The two studies were identical in design and conducted simultaneously, and the results were analyzed both pooled and individually.

Hemodynamic Effects

As shown in Table 5, chronic therapy with Remodulin resulted in small hemodynamic changes consistent with pulmonary and systemic vasodilation.

Table 5: Hemodynamics during Chronic Administration of Remodulin in Patients with PAH in 12-Week Studies

Hemodynamic Parameter Baseline Mean change from baseline at Week 12
CI (L/min/m²) 2.4 ± 0.88 2.2 ± 0.74 +0.12 ± 0.58* -0.06 ± 0.55
PAPm (mmHg) 62 ± 17.6 60 ± 14.8 -2.3 ± 7.3* +0.7 ± 8.5
RAPm (mmHg) 10 ± 5.7 10 ± 5.9 -0.5 ± 5.0* + 1.4 ± 4.8
PVRI (mmHg/L/min/m²) 26 ± 13 25 ± 13 -3.5 ± 8.2* + 1.2 ± 7.9
SVRI (mmHg/L/min/m²) 38 ± 15 39 ± 15 -3.5 ± 12* -0.80 ± 12
SvO2 (%) 62 ± 100 60 ± 11 +2.0 ± 10* -1.4 ± 8.8
SAPm (mmHg) 90 ± 14 91 ± 14 -1.7 ± 12 -1.0 ± 13
HR (bpm) 82 ± 13 82 ± 15 -0.5 ± 11 -0.8 ± 11
*Denotes statistically significant difference between Remodulin and placebo, p < 0.05. CI = cardiac index; PAPm = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance indexed; RAPm = mean right atrial pressure; SAPm = mean systemic arterial pressure; SVRI = systemic vascular resistance indexed; SvO2 = mixed venous oxygen saturation; HR = heart rate.

Clinical Effects

The effect of Remodulin on 6-minute walk, the primary end point of the 12-week studies, was small and did not achieve conventional levels of statistical significance. For the combined populations, the median change from baseline on Remodulin was 10 meters and the median change from baseline on placebo was 0 meters from a baseline of approximately 345 meters. Although it was not the primary endpoint of the study, the Borg dyspnea score was significantly improved by Remodulin during the 6-minute walk, and Remodulin also had a significant effect, compared with placebo, on an assessment that combined walking distance with the Borg dyspnea score. Remodulin also consistently improved indices of dyspnea, fatigue and signs and symptoms of pulmonary hypertension, but these indices were difficult to interpret in the context ofincomplete blinding to treatment assignment resulting from infusion site symptoms.

Flolan-To-Remodulin Transition Study

In an 8-week, multicenter, randomized, double-blind, placebo-controlled study, patients on stabledoses of Flolan were randomly withdrawn from Flolan to placebo or Remodulin. Fourteen Remodulin and 8 placebo patients completed the study. The primary endpoint of the study was the time to clinical deterioration, defined as either an increase in Flolan dose, hospitalization due to PAH, or death. No patients died during the study.

During the study period, Remodulin effectively prevented clinical deterioration in patients transitioning from Flolan therapy compared to placebo (Figure 1). Thirteen of 14 patients in the Remodulin arm were able to transition from Flolan successfully, compared to only 1 of 8 patients in the placebo arm (p=0.0002).

Figure 1: Time to Clinical Deterioration for PAH Patients Transitioned from Flolan to Remodulin or Placebo in an 8-Week Study

Time to Clinical Deterioration - Illustration

Last reviewed on RxList: 2/5/2016
This monograph has been modified to include the generic and brand name in many instances.

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