Pramipexole - How It Works
Clinical pharmacology details from the US FDA-approved label: how Pramipexole works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D 2 subfamily of dopamine receptors, binding with higher affinity to D 3 than to D 2 or D 4 receptor subtypes.
Parkinson’s Disease The precise mechanism of action of pramipexole as a treatment for Parkinson’s disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum.
This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.
The relevance of D 3 receptor binding in Parkinson’s disease is unknown.
Restless Legs Syndrome (RLS) The precise mechanism of action of pramipexole dihydrochloride tablets as a treatment for RLS is unknown.
Although the pathophysiology of RLS 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 RLS.
12.2 Pharmacodynamics The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers.
All subjects initiated treatment with 0.375 mg extended release pramipexole tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label.
No dose- or exposure-related effect on mean QT intervals was observed; however, the study did not have a valid assessment of assay sensitivity.
The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.
Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively.
Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values.
Such effects have not been observed in clinical studies with Parkinson’s disease patients, who were titrated according to labeled recommendations.
12.3 Pharmacokinetics Pramipexole displays linear pharmacokinetics over the clinical dosage range.
Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers.
Steady-state concentrations are achieved within 2 days of dosing.
Absorption Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours.
The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism.
Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (T max ) is increased by about 1 hour when the drug is taken with a meal.
Pharmacokinetics
12.3 Pharmacokinetics Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are achieved within 2 days of dosing. Absorption Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (T max ) is increased by about 1 hour when the drug is taken with a meal. Distribution Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV]=20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2. Metabolism Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine. Elimination Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, pro