Sign Out
Pharmacotherapeutic group: Dopamine agonist. ATC code: N04BC05.
Pharmacology: Mode of Action: Pramipexole, 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 inhibits dopamine synthesis, release, and turnover. Pramipexole protects dopamine neurones from degeneration in response to ischemia or metamphetamine neurotoxicity.
In vitro studies demonstrate that pramipexole protects neurones from levodopa neurotoxicity.
Pharmacodynamics: 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.
Clinical Trials: 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 extended-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 extended-release tablets experienced a drug-related adverse event leading to withdrawal.
Pharmacokinetics: Absorption: Pramipexole is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90%.
The maximum plasma concentrations occur at about 6 hours. Generally, food does not affect the bioavailability of pramipexole. A slight increase of about 20% in peak concentration and a delay of about 2 hours in time to reach peak concentration after a high fat meal are not considered clinically relevant.
Pramipexole shows linear kinetics and a relatively small inter-patient variation of plasma levels irrespective of the pharmaceutical form.
Distribution: In humans the protein binding of pramipexole 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).
Biotransformation: Pramipexole is metabolised in man only to a small extent.
Elimination: Renal excretion of unchanged pramipexole 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 feces. The total clearance of pramipexole 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. Age - Pramipexole clearance is reduced by approximately 30% in the elderly (aged 65 years or older) compared with young healthy volunteers (age less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.
