Mechanism of Action: REQUIP is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D₂ and D₃ dopamine receptor subtypes, binding with higher affinity to D₃ than to D₂ or D₄ receptor subtypes.

Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D₁, 5-HT₁, 5-HT₂, benzodiazepine, GABA, muscarinic, alpha₁-, alpha₂-, and beta-adrenoreceptors.

Parkinson's Disease: The precise mechanism of action of REQUIP as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D₂-type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that ropinirole improves motor function in various animal models of Parkinson's disease. In particular, ropinirole attenuates the motor deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates. The relevance of D₃ receptor binding in Parkinson's disease is unknown.

Restless Legs Syndrome (RLS): The precise mechanism of action of REQUIP as a treatment for Restless Legs Syndrome (also known as Ekbom Syndrome) 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.

Clinical Pharmacology Studies: In healthy normotensive subjects, single oral doses of REQUIP in the range 0.01 to 2.5 mg had little or no effect on supine blood pressure and pulse rates. Upon standing, REQUIP caused decreases in systolic and diastolic blood pressure at doses above 0.25 mg. In some subjects, these changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case, transient sinus arrest with syncope. With repeat dosing and slow titration up to 4 mg once daily in healthy volunteers, postural hypotension or hypotension-related adverse events were noted in 13% of subjects on REQUIP and none of the subjects on placebo.

The mechanism of postural hypotension induced by REQUIP is presumed to be due to a D₂-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant of orthostatic signs and symptoms.

At oral doses as low as 0.2 mg, REQUIP suppressed serum prolactin concentrations in healthy male volunteers.

REQUIP had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg.

REQUIP had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of REQUIP on QT intervals at higher exposures achieved either due to drug interactions or at doses used in Parkinson's disease has not been systematically evaluated.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination: The pharmacokinetics of ropinirole are similar in Parkinson's disease patients and patients with Restless Legs Syndrome. Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1-2 hours. In clinical studies, over 88% of a radiolabeled dose was recovered in urine and the absolute bioavailability was 55%, indicating a first-pass effect. Relative bioavailability from a tablet compared to an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal. The clearance of ropinirole after oral administration to patients is 47 L/hr (cv = 45%) and its elimination half-life is approximately 6 hours. Ropinirole is extensively metabolized by the liver to inactive metabolites and displays linear kinetics over the therapeutic dosing range of 1 to 8 mg 3 times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing.

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