"The U.S. Food and Drug Administration today approved Opsumit (macitentan), a new drug to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive and debilitating disease that can lead to death or the need for lung transpla"...
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Mechanism of Action
Iloprost is a synthetic analog of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer.
In pharmacokinetic studies in animals, there was no evidence of interconversion of the two diastereoisomers of iloprost. In human pharmacokinetic studies, the two diastereoisomers were not individually assayed.
Iloprost administered intravenously has linear pharmacokinetics over the dose range of 1 to 3 ng/kg/min. The half-life of iloprost is 20 to 30 minutes. Following inhalation of iloprost (5 mcg) patients with pulmonary hypertension have iloprost peak plasma levels of approximately 150 pg/mL. Iloprost was generally not detectable in plasma 30 minutes to 1 hour after inhalation.
Absorption and Distribution
The absolute bioavailability of inhaled iloprost has not been determined. Following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 L/kg in healthy subjects. Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is concentration-independent in the range of 30 to 3000 pg/mL.
Metabolism and Excretion
In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Iloprost is metabolized principally via β-oxidation of the carboxyl side chain. The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form. In animal experiments, tetranor-iloprost was pharmacologically inactive.
Clearance in normal subjects was approximately 20 mL/min/kg.
A mass-balance study using intravenously and orally administered [3H]-iloprost in healthy subjects (n=8) showed recovery of 81% of total radioactivity over 14 hours post-dose, with 68% and 12% recoveries in urine and feces, respectively.
A randomized, double-blind, multi-center, placebo-controlled trial was conducted in 203 adult patients (inhaled iloprost: n=101; placebo: n=102) with NYHA Class III or IV pulmonary arterial hypertension (PAH, WHO Group 1; idiopathic in 53%, associated with connective tissue disease, including CREST and scleroderma, in 17%, or associated with anorexigen use in 2%) or PAH related to chronic thromboembolic disease (WHO Group 4; 28%). Inhaled iloprost (or placebo) was added to patients' current therapy, which could have included anticoagulants, vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digoxin, but not PGI2 (prostacyclin or its analogs) or endothelin receptor antagonists. Patients received 2.5 or 5.0 mcg of iloprost by repeated inhalations 6 to 9 times per day during waking hours. The mean age of the entire study population was 52 years and 68% of the patients were female. The majority of patients (59%) were NYHA Class III. The baseline 6-minute walk test values reflected a moderate exercise limitation (the mean was 332 meters for the iloprost group and 315 meters for the placebo group). In the iloprost group, the median daily inhaled dose was 30 mcg (range of 12.5 to 45 mcg/day). The mean number of inhalations per day was 7.3. Ninety percent of patients in the iloprost group never inhaled study medication during the nighttime.
The primary efficacy endpoint was clinical response at 12 weeks, a composite endpoint defined by: a) improvement in exercise ability (6-minute walk test) by at least 10% versus baseline evaluated 30 minutes after dosing, b) improvement by at least one NYHA class versus baseline, and c) no death or deterioration of pulmonary hypertension. Deterioration required two or more of the following criteria: 1) refractory systolic blood pressure < 85 mmHg, 2) worsening of right heart failure with cardiac edema, ascites, or pleural effusion despite adequate background therapy, 3) rapidly progressive cardiogenic hepatic failure (e.g., leading to an increase of GOT or GPT to > 100 U/L, or total bilirubin ≥ 5 mg/dL), 4) rapidly progressive cardiogenic renal failure (e.g., decrease of estimated creatinine clearance to ≤ 50% of baseline), 5) decrease in 6-minute walking distance by ≥ 30% of baseline value, 6) new long-term need for i.v. catecholamines or diuretics, 7) cardiac index ≤ 1.3 L/min/m², 8) CVP ≥ 22 mmHg despite adequate diuretic therapy, and 9) SVO2 ≤ 45% despite nasal O2 therapy.
Although effectiveness was seen in the full population (response rates for the primary composite endpoint of 17% and 5%; p=0.007), there was inadequate evidence of benefit in patients with pulmonary hypertension associated with chronic thromboembolic disease (WHO Group 4); the results presented are therefore those related to patients with PAH (WHO Group 1). The response rate for the primary efficacy endpoint among PAH patients was 19% for the iloprost group, compared with 4% for the placebo group(p=0.0033). All three components of the composite endpoint favored iloprost (Figure 1)
Figure 1: Composite Primary Endpoint for PAH Patients
(WHO Group I)
The absolute change in 6-minute walk distance (Figure 2) measured (using all available data and no imputation) 30 minutes after inhalation among patients with PAH was greater in the iloprost group compared to the placebo group at all time points. At Week 12, the placebo-corrected difference was 40 meters (p < 0.01). When walk distance was measured immediately prior to inhalation, the improvement compared to placebo was approximately 60% of the effect seen at 30 minutes after inhalation.
Figure 2: Change (Mean ± SEM) in 6-Minute Walk
Distance 30 Minutes Post-inhalation in PAH Patients (WHO Group 1).
The effect of Ventavis in various subgroups is shown in Table 2.
Table 2: Treatment Effects
by Subgroup among PAH Patients (WHO Group 1)
|Composite Clinical Endpoint||6-Minute Walk (m)*|
|n||Ventavis n (%)||n||Placebo n (%)||n||Ventavis (mean ±SD)||n||Placebo (mean ±SD)|
|All Subjects with PAH**||68||13 (19%)||78(4%)||3||64||31 ± 76||65||-9 ± 79|
|NYHA III||40||7 (18%)||47||2 (4%)||39||24 ± 72||43||-16 ± 86|
|NYHA IV||28||6 (21%)||31||1 (3%)||25||43 ± 82||22||6 ± 63|
|Male||23||5 (22%)||24||0 (0%)||21||37 ± 81||21||-22 ± 77|
|Female||45||8 (18%)||54||3 (6%)||43||29 ± 74||44||-2 ± 81|
|Age ≤ 55||41||6 (15%)||40||2 (5%)||39||24 ± 79||32||-5 ± 78|
|Age > 55 -26%||27||7||38||1 (3%)||25||42 ± 71||33||-13 ± 81|
|* Change from baseline to 12 Weeks with measurement 30
minutes after dosing, based on all available data.
** Etiologies of PAH, WHO Group 1 included idiopathic in 62% (n=90), associated with connective tissue disease, including CREST and scleroderma, in 17%, (n=25), associated with anorexigen use in 6% (n=9), heritable PAH in 3% (n=5), other PPH in 3% (n=5), SLE in 1% (n=2), post-partum in 1% (n=2), and overlap/other in 5% (n=8).
Hemodynamic assessments obtained at week 12 before inhalation in both groups (at least 2 hours after a previous dose, trough) and after inhalation in the iloprost group (approximately 15 minutes after a dose, peak), are shown in Table 3. The relationship between hemodynamic changes and clinical effects is unknown.
Table 3 : Hemodynamic Parameters Before and After
Iloprost Inhalation: Change from Baseline to Week 12*
|Parameter||Baseline||Mean (± SD) change from baseline at Week 12|
|Before Inhalation||After Inhalation|
|PVR (dyn•s•cm–5)||1029 ± 390||1041 ± 493||-9 ± 275 (n=76)||-239 ± 279 (n=70)||+96 ± 323 (n=77)|
|mPAP (mmHg)||53 ± 12||54 ± 14||-0.2 ± 7.3 (n=93)||-4.6 ± 9.3 (n=90)||-0.1 ± 6.9 (n=82)|
|CO (L/min)||3.8 ± 1.1||3.8 ± 0.9||+0.1 ± 0.9 (n=91)||+0.5 ± 1.1 (n=89)||-0.2 ± 0.8 (n=80)|
|SVO2 (%)||60 ± 8||60±8||-1.1 ± 7.6 (n=72)||+1.8 ± 8.3 (n=70)||-3.2 ± 6.7 (n=63)|
|*Patients of all etiologies of PAH, including CTEPH.|
In a small, randomized, double-blind, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 mg bid for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6.
Last reviewed on RxList: 12/12/2013
This monograph has been modified to include the generic and brand name in many instances.
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