General

Iloprost is a synthetic analogue 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 diastereo isomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer.

Pharmacokinetics

General

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 serum levels of approximately 150 pg/mL. Iloprost was generally not detectable in the 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

Clearance in normal subjects was approximately 20 mL/min/kg. 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.

In vitrostudies reveal that cytochrome P450-dependent metabolism plays only a minor role in the biotransformation of iloprost.

A mass-balance study using intravenously and orally administered [³H]-iloprost in healthy subjects (n=8) showed recovery of total radioactivity over 14 hours post-dose, was 81%, with 68% and 12% recoveries in urine and feces, respectively.

Special Populations

Liver Function Impairment

Inhaled iloprost has not been evaluated in subjects with impaired hepatic function. However, in an intravenous iloprost study in patients with liver cirrhosis, the mean clearance in Child Pugh Class B subjects (n=5) was approximately 10 mL/min/kg (half that of healthy subjects). Following oral administration, the mean AUC_0-8h in Child Pugh Class B subjects (n=3) was 1725 pg*h/mL compared to 117 pg*h/mL in normal subjects (n=4) receiving the same oral iloprost dose. In Child Pugh Class A subjects (n=5), the mean AUC_0-8h was 639 pg*h/mL. Although exposure increased with hepatic impairment, there was no effect on half-life.

Renal Function Impairment

Inhaled iloprost has not been evaluated in subjects with impaired renal function. However, in a study with intravenous infusion of iloprost in patients with end-stage renal failure requiring intermittent dialysis treatment (n=7), the mean AUC0-4h was 230 pg*h/mL compared to 54 pg*h/mL inpatients with renal failure (n=8) not requiring intermittent dialysis and 48 pg*h/mL in normals. The half-life was similar in both groups. The effect of dialysis on iloprost exposure has not been evaluated.

Clinical Trials

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 I; idiopathic in 53%, associated with connective tissue disease, including CREST and scleroderma, in 17%, or associated with anorexigen use in 2%) or pulmonary hypertension related to chronic thromboembolic disease (WHO Group IV; 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 digitalis, but not PGI2 (prostacyclin or its analogues) 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.

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