Chemical formula: C₂₂H₃₂O₄ Molecular mass: 360.494 g/mol PubChem compound: 5311181
Iloprost is a synthetic prostacyclin analogue.
The following pharmacological effects have been observed:
The pharmacological effects after inhalation of iloprost are: Direct vasodilatation of the pulmonary arterial bed occur with consecutive significant improvement of pulmonary artery pressure, pulmonary vascular resistance and cardiac output as well as mixed venous oxygen saturation.
No clinical trial data are available comparing directly in intra-patient observations the acute haemodynamic response after intravenous to that after inhaled iloprost. The haemodynamics observed suggest an acute response with preferential effect of inhaled treatment on the pulmonary vessels. The pulmonary vasodilatory effect of each single inhalation levels off within one to two hours.
However, the predictive value of these acute haemodynamic data are considered to be of limited value as acute response does not in all cases correlate with long-term benefit of treatment with inhaled iloprost.
When iloprost at the concentration of 10 microgram/ml is administered via inhalation in patients with pulmonary hypertension or healthy volunteers (iloprost dose at the mouthpiece: 5 microgram: inhalation time in between 4.6–10.6 min), mean peak serum concentrations of about 100 to 200 picogram/ml were observed at the end of inhalation session. These concentrations decline with half-lives between approximately 5 and 25 minutes. Within 30 minutes to 2 hours after the end of inhalation, iloprost is not detectable in the central compartment (limit of quantification 25 picogram/ml).
No studies performed following inhalation.
Steady-state plasma levels are achieved as early as 10-20 minutes after the start of an intravenous infusion. The steady-state plasma levels are linearly related to the infusion rate. Plasma levels of about 135 ± 24 pg/ml are obtained at an infusion rate of 3 ng/kg/min. The plasma concentration of iloprost drops very rapidly after the end of the infusion, because of the high rate of metabolism. The metabolic clearance of the substance from plasma is about 20 ± 5 ml/kg/min. The half-life of the terminal elimination phase from plasma is 0.5 hours, as a result of which the plasma level falls to less than 10% of the steady-state concentration, just two hours after the end of infusion.
Interactions with other medicines at the level of plasma protein binding are minimal, because the greater portion of iloprost is bound to the plasma albumin (protein binding: 60%) and only very low iloprost concentration is reached.
An effect of iloprost therapy on the biotransformation of other medicines is also extremely unlikely because of the metabolic pathways and the low absolute dose.
No studies to investigate the metabolism of iloprost were performed following inhalation.
After intravenous administration, iloprost is extensively metabolised via β-oxidation of the carboxyl side chain. No unchanged substance is eliminated. The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form. Tetranor-iloprost is pharmacologically inactive as shown in animal experiments. Results of in vitro studies reveal that CYP 450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Further in vitro studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.
No studies performed following inhalation.
In subjects with normal renal and hepatic function, the disposition of iloprost following intravenous infusion is characterised in most cases by a two-phase profile with mean half-lives of 3 to 5 minutes and 15 to 30 minutes. The total clearance of iloprost is about 20 ml/kg/min, which indicates extrahepatic contribution to the metabolism of iloprost. A mass-balance study was conducted using 3H-iloprost in healthy subjects. Following intravenous infusion, the recovery of total radioactivity is 81%, and the respective recoveries in urine and faeces are 68% and 12%. The metabolites are eliminated with plasma and with urine in 2 phases for which half-lives of about 2 and 5 hours (plasma) and 2 and 18 hours (urine) have been calculated.
Pharmacokinetics of iloprost were investigated in a randomised, crossover study with 27 patients, stable on iloprost 10 microgram/ml inhaled with I-Neb, following inhalation of single doses of 2.5 or 5 microgram iloprost using the Breelib or the I-Neb AAD nebuliser. Following inhalation of these doses with the Breelib the maximum plasma concentrations (Cmax) and systemic exposures (AUC (0-tlast)) increased dose-proportionally.
Cmax and AUC (0-tlast) after inhalation of 5 microgram iloprost administered as iloprost 20 microgram/ml using the Breelib were 77% and 42%, respectively higher compared to inhalation of the same dose using iloprost 10 microgram/ml and the I-Neb AAD system. Cmax and AUC (0-tlast) of iloprost after inhalation with Breelib were, however, still in the range of values observed with iloprost 10 microgram/ml using other inhalers across different studies.
Pharmacokinetics under the specific study conditions of extended inhalation time, were investigated in a randomised, crossover study with 19 healthy adult men following inhalation of single doses of iloprost 10 microgram/ml and iloprost 20 microgram/ml (dose of 5 microgram iloprost at the mouthpiece) using the I-Neb. Comparable systemic exposures (AUC (0-tlast)) and approximately 30% higher maximum serum concentrations (Cmax) were found following inhalation of iloprost 20 microgram/ml compared to iloprost 10 microgram/ml which was in line with the observed shorter inhalation time using iloprost 20 microgram/ml.
In a study with intravenous infusion of iloprost, patients with end stage renal failure undergoing intermittent dialysis treatment are shown to have a significantly lower clearance (mean CL = 5 ± 2 ml/min/kg) than that observed in patients with renal failure not undergoing intermittent dialysis treatment (mean CL = 18 ± 2 ml/min/kg).
Because iloprost is extensively metabolised by the liver, the plasma levels of the medicine are affected by changes in hepatic function. In an intravenous administration study, results were obtained involving 8 patients suffering from liver cirrhosis. The mean clearance of iloprost was estimated to be 10 ml/min/kg.
Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenicity. Preclinical study effects were observed only at exposures considered considerably higher than the maximum human exposure indicating little relevance to clinical use.
In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (intravenous) at doses about two orders of magnitude above the intravenous therapeutic dose. Considering the high pharmacological potency of iloprost and the absolute doses required for therapeutic purposes the results obtained in acute toxicity studies do not indicate a risk of acute adverse effects in humans. As expected for a prostacyclin, iloprost produced haemodynamic effects (vasodilatation, reddening of skin, hypotension, inhibition of platelet function, respiratory distress) and general signs of intoxication such as apathy, gait disturbances, and postural changes.
Continuous intravenous/subcutaneous infusion of iloprost up to 26 weeks in rodents and non-rodents did not cause any organ toxicity at dose levels which exceeded the human therapeutic systemic exposure between 14 and 47 times (based on plasma levels). Only expected pharmacological effects like hypotension, reddening of skin, dyspnoea, increased intestinal motility were observed.
In a chronic inhalation study in rats over 26 weeks, the highest achievable dose of 48.7 microgram/kg/day was identified as ‘no observed adverse effect level’ (NOAEL). Systemic exposures exceeded human therapeutic exposures after inhalation by factors of more than 10 (Cmax, cumulative AUC).
In vitro (bacterial, mammalian cells, human lymphocytes) and in vivo studies (micronucleus test) for genotoxic effects have not produced any evidence for a mutagenic potential.
No tumourigenic potential of iloprost was observed in tumourigenicity studies in rats and mice.
In embryo- and foetotoxicity studies in rats continuous intravenous administration of iloprost led to anomalies of single phalanges of the forepaws in a few foetuses/pups without dose dependence.
These alterations are not considered as teratogenic effects, but are most likely related to iloprost induced growth retardation in late organogenesis due to haemodynamic alterations in the foetoplacental unit. No disturbance of postnatal development and reproductive performance was seen in the offspring that were raised, indicating that the observed retardation in rats was compensated during the postnatal development. In comparable embryotoxicity studies in rabbits and monkeys no such digit anomalies or other gross-structural anomalies were observed even after considerably higher dose levels which exceeded the human dose multiple times. In rats, passage of low levels of iloprost and/or metabolites into the milk was observed (less than 1% of iloprost dose given intravenously). No disturbance of post-natal development and reproductive performance was seen in animals exposed during lactation.
Local tolerance, contact sensitising and antigenicity potential
In inhalation studies in rats, the administration of an iloprost formulation with a concentration of 20 microgram/ml up to 26 weeks did not cause any local irritation of the upper and lower respiratory tract.
A dermal sensitisation (maximisation test) and an antigenicity study in guinea pigs showed no sensitising potential.
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