Sifrol Mechanism of Action

Pharmacotherapeutic group: dopamine agonist. ATC code: N04BC05
Pharmacology: Pramipexole dihydrochloride monohydrate, the active ingredient of SIFROL, is a dopamine agonist and binds with high selectivity and specificity to the dopamine D2 subfamily receptors and has a preferential affinity to D3 receptors; it has full intrinsic activity.
SIFROL alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole dihydrochloride monohydrate inhibits dopamine synthesis, release, and turnover. Pramipexole dihydrochloride monohydrate protects dopamine neurones from degeneration in response to ischemia or methamphetamine neurotoxicity.
The precise mechanism of action of SIFROL as a treatment for Restless Legs Syndrome is not known. Although the pathophysiology of Restless Legs Syndrome is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of Restless Legs Syndrome.
In vitro studies demonstrate that pramipexole dihydrochloride monohydrate protects neurones from levodopa neurotoxicity.
In human volunteers a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where SIFROL Extended-release tablets were titrated faster than recommended (every 3 days) up to 4.5 mg per day, an increase in blood pressure and heart rate was observed. Such effect was not observed in patient studies.
Parkinson's disease: Efficacy of SIFROL in the controlled clinical trials was maintained for the duration of the trials, approximately six months. In open continuation trials lasting for more than three years there were no signs of decreasing efficacy.
The efficacy and tolerability of an overnight switch from SIFROL tablets to SIFROL Extended-release tablets at the same daily dose was evaluated in a double-blind clinical study in patients with early Parkinson's disease.
Efficacy was maintained in 87 of 103 patients switched to SIFROL prolonged-release tablets. Out of these 87 patients, 82.8% did not change their dose, 13.8% increased and 3.4% decreased their dose. In half of the 16 patients who did not meet the criterion for maintained efficacy on UPDRS Part II+III score, the change from baseline was considered not clinically relevant.
One patient switched to SIFROL prolonged-release tablets experienced a drug-related adverse event leading to withdrawal.
Restless Legs Syndrome: The efficacy of SIFROL was evaluated in four placebo controlled trials in approximately 1000 patients with moderate to very severe Restless Legs Syndrome. Efficacy was demonstrated in controlled trials in patients treated for up to 12 weeks and sustained efficacy was shown over a period of 9 months.
The efficacy of SIFROL was maintained during open continuation trials lasting for up to 1 year. In a placebo controlled clinical trial over 26 weeks, the efficacy of pramipexole dihydrochloride monohydrate was confirmed in patients with moderate to severe RLS.
Pharmacokinetics: Pramipexole dihydrochloride monohydrate is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90 %.
Tablets: The maximum plasma concentrations occur between 1 and 3 hours. The rate of absorption is reduced by food intake but not the overall extent of absorption.
Pramipexole dihydrochloride monohydrate shows linear kinetics and a relatively small inter-patient variation of plasma levels irrespective of the pharmaceutical form.
In humans the protein binding of pramipexole dihydrochloride monohydrate is very low (< 20 %) and the volume of distribution is large (400L). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to plasma).
Pramipexole dihydrochloride monohydrate is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole dihydrochloride monohydrate is the major route of elimination and accounts for about 80% of dose. Approx. 90% of a 14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole dihydrochloride monohydrate is approx. 500 ml/min and the renal clearance is approx. 400 ml/min. The elimination half-life (t ½) varies from 8 hours in the young to 12 hours in the elderly.
Toxicology: Repeated dose toxicity studies showed that pramipexole dihydrochloride monohydrate exerted functional effects, mainly involving the CNS and, in the rat, the female reproductive system, probably resulting from an exaggerated pharmacodynamic effect of pramipexole dihydrochloride monohydrate.
Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to a hypotensive effect was discerned in the monkey.
The potential effects of pramipexole dihydrochloride monohydrate on reproductive function have been investigated in rats and rabbits. Pramipexole dihydrochloride monohydrate was not teratogenic in rats and rabbits but was embryotoxic in the rat at maternally toxic doses. Due to the hypoprolactinaemic effect of the compound and the special role of prolactin in reproductive function in the female rat, the effects of pramipexole dihydrochloride monohydrate on pregnancy and female fertility were not fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.
Pramipexole dihydrochloride monohydrate was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole dihydrochloride monohydrate. This finding is not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of the salt form) and higher, pramipexole dihydrochloride monohydrate was associated with retinal degeneration in albino rats. The latter finding was not observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study, or in any other species investigated.