Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: Bayer New Zealand Limited, 3 Argus Place, Hillcrest, North Shore, Auckland 0627, Free Phone 0800 229 376, www.bayer.co.nz
Iloprost is a synthetic prostacyclin analogue. The following pharmacological effects have been observed:
Iloprost, due to its anti-aggregatory effects and potent pulmonary vasodilatory effect, has demonstrated beneficial haemodynamic effects and an improvement in exercise tolerance in patients suffering from severe pulmonary hypertension (PHT). In addition, recent studies have reported that this action on the pulmonary circulation can be augmented by the inhalative delivery of iloprost. Treatment with iloprost results in a reduction in pulmonary vascular resistance and pulmonary artery pressure, an increase in cardiac output and an improvement in oxygenation.
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 falls very quickly 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 disposition phase from plasma is 0.5 hours, as a result of which the substance level falls to less than 10% of the equilibrium concentration just two hours after the end of infusion.
Interactions with other medicines at the level of plasma protein binding are improbable because the greater portion of iloprost is bound to the albumin of blood plasma (protein binding: 60%) and only very low iloprost concentrations are achieved. An effect of iloprost therapy on the biotransformation of other medicines is likewise extremely unlikely because of the metabolic pathways and the low absolute dose.
Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 L/kg in healthy subjects. Total plasma protein binding of iloprost is concentration independent in the range of 30 to 3000 pg/mL and amounts to approximately 60%, of which 75% is due to albumin binding.
Iloprost is extensively metabolised principally via ß-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 in 4 diastereoisomers. Tetranor-iloprost is pharmacologically inactive as shown in animal experiments. In vivo studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or 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 done 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 from 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.
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 influenced by changes in hepatic function. In an intravenous study, results were obtained involving 8 patients suffering from liver cirrhosis. The mean clearance of iloprost is 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, carcinogenic potential. Preclinical effects were observed only at exposures considered sufficiently in excess of 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 (i.v.) at dosages 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.
In systemic toxicity studies with repeated (continuous) i.v. infusion, a slight reduction of the blood pressure occurred at doses above 14 ng/kg/min. and severe undesired effects (hypotension, disturbance of respiratory function) appeared only after extremely high dosages.
Continuous i.v./s.c.infusion of iloprost up to 26 weeks in rodents and non-rodents at dose levels which exceeded the human therapeutic systemic exposure between 14 and 47 times (based on plasma levels) did not cause any organ toxicity. Only expected pharmacological effects like hypotension, reddening of skin, dyspnoea and increased intestinal motility were observed.
In vitro and in vivo studies for genotoxic effects have not produced any evidence for a mutagenic potential.
No tumourigenic potential of iloprost could be demonstrated in tumourigenicity studies in rats and mice.
In embryo- and foetotoxicity studies in rats continuous intravenous administration if iloprost led to anomalies of single phalanges of the forepaws in a few foetuses/pups without dose-dependence.
These alterations are not considered as true teratogenic effects, but are most likely related to iloprost induced growth retardation in late organogensis due to haemodynamic alterations in the foetoplacental unit. It can be assumed that this growth retardation is widely reversible during the postnatal development. In comparable embryotoxicity studies in rabbits and monkeys no such digit anomalies or other gross-structurally abnormalities were observed even after considerably higher dose levels which exceeded the human dose multiple times.
In rats a passage of extremely low levels of iloprost into the milk were observed.
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