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Pharmacology: Pharmacodynamics: Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and turnover.
The mechanism of action of pramipexole as a treatment for Restless Legs Syndrome is unknown. Neuropharmacological evidence suggests primary dopaminergic system involvement.
In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where OPRYMEA prolonged-release tablets were titrated faster (every 3 days) than recommended up to 4.5 mg of salt per day, an increase in blood pressure and heart rate was observed. Such an effect was not observed in patient studies.
In patients, pramipexole alleviates signs and symptoms of idiopathic Parkinson's disease.
Pharmacokinetics: Pramipexole is completely absorbed following oral administration. The absolute bioavailability is greater than 90%.
In a Phase I trial, where pramipexole immediate-release and prolonged-release tablets were assessed in a fasted state, the minimum and peak plasma concentration (Cmin, Cmax) and exposure (AUC) of the same daily dose of OPRYMEA prolonged-release tablets given once daily and OPRYMEA tablets given three times a day were equivalent.
The once-daily administration of OPRYMEA prolonged-release tablets causes less frequent fluctuations in the pramipexole plasma concentration over 24 hours compared to the three times daily administration of pramipexole immediate-release tablets.
The maximum plasma concentrations occur at about 6 hours after administration of OPRYMEA prolonged-release tablets once daily and 1 to 3 hours after taking tablets.
A steady state of exposure is reached at the latest after 5 days of continuous dosing.
Concomitant administration with food does generally not affect the bioavailability of pramipexole. Intake of a high-fat meal-induced an increase in peak concentration (Cmax) of about 24% after a single dose administration and about 20% after multiple dose administrations and a delay of about 2 hours in time to reach peak concentration in healthy volunteers. Total exposure (AUC) was not affected by concomitant food intake. The increase in Cmax is not considered clinically relevant. In the Phase III studies that established the safety and efficacy of OPRYMEA prolonged-release tablets, patients were instructed to take study medication without regard to food intake.
While body weight has no impact on the AUC, it was found to influence the volume of distribution and therefore the peak concentrations Cmax. A decreased body weight by 30 kg results in an increase in Cmax of 45%. However, in Phase III trials in Parkinson's disease patients no clinically meaningful influence of body weight on the therapeutic effect and tolerability of OPRYMEA prolonged-release tablets was detected.
Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.
In humans, the protein binding of pramipexole is very low (<20%) and the volume of distribution is large (400 L). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to plasma).
Pramipexole is metabolized in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of the 14C-labelled dose is excreted through the kidneys while less than 2% is found in the feces. The total clearance of pramipexole is approximately 500 mL/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
