Kinetica Mechanism of Action

Anti-parkinson drug (dopamine agonist).
Pharmacology: Pharmacodynamics: Ropinirole, a dipropylaminoethyl indolone derivative, is a non-ergoline D₂/D₃ dopamine receptor agonist. Although the exact mechanism of action of ropinirole is unknown, its antiparkinson activity is thought to be associated with its ability to stimulate central postsynaptic dopamine D₂ receptors in the corpus striatum of the brain.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin. Neither ropinirole nor its metabolites has high affinity to dopamine D₁ receptors. Ropinirole binds to opiate receptors with low affinity. However, in vivo studies showed that the weak opiate activity has no effect at pharmacological doses. Ropinirole has little or no affinity for serotonin type 1 (5-HT₁), serotonin type 2 (5-HT₂), benzodiazepine, gamma-aminobutyric acid, muscarinic, alpha-or beta-adrenoceptors.
Pharmacokinetics: Bioavailability of ropinirole is approximately 50% (range: 36% to 57%). Following oral administration, ropinirole plasma concentrations increase slowly, with a median time to peak plasma concentration (t_max) generally achieved between 6 to 10 hours.
Ropinirole hydrochloride 2 mg, 4 mg, and 8 mg prolonged-release tablets (KRKA, Slovenia) were shown to be bioequivalent to the reference product (innovator).
In two different studies, a single dose of ropinirole hydrochloride 2 mg and 4 mg prolonged-release tablets were administered in adult male volunteers under fasting conditions. The results showed that 90% Confidence Interval for the geometric means of maximum plasma concentration (C_max), area under the concentration-time curve from time 0 to the last measurable concentration (AUC_0-1) and AUC from time 0 to infinity (AUC_0-inf) of ropinirole 2 mg and 4 mg prolonged-release tablets are within the predefined bioequivalence limits of 80 to 125%. (See Table 1.)

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In a separate study, 8 mg prolonged-release tablets were administered for five consecutive days. The results showed that 90% Confidence Interval for the geometric means of maximum plasma concentration at steady state (C_{max, ss}), minimum plasma concentration at steady state (C_{min, ss}), and area under the concentration-time curve from one dosing interval at steady-state (AUC_0-Tss) of ropinirole 8 mg prolonged-release tablet are within the predefined bioequivalence limits of 80 to 125%. (See Table 2.)

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Compared with dosing under fasting conditions, high-fat meal increased the systemic exposure of ropinirole 12 mg prolonged-release tablet in Parkinson's disease patients, as shown by the increase in the AUC and peak plasma concentration (C_max) by 20% and 44% on average, respectively. Although t_max was delayed by 3 hours, these changes are unlikely to be clinically relevant (e.g., increased incidence of adverse events) and patients were instructed to take ropinirole prolonged-release tablet without regard to food intake.
The systemic exposure of ropinirole prolonged-release tablets is comparable to that of ropinirole immediate-release tablets based on the same daily dose. Ropinirole is highly lipophilic, thus the drug has a large volume of distribution (approximately 7 L/kg). The plasma protein binding of ropinirole is 10 to 40%.
Steady-state concentrations of ropinirole are expected to be attained within 4 days of dosing. The increase in systemic exposure (C_max and AUC) to ropinirole is in proportion over the therapeutic dose range. Thus, patients taking ropinirole three times a day has two-fold higher steady-state plasma concentrations compared to those observed in patients taking a single oral dose. The average oral clearance (47 L/h) of ropinirole is constant over the entire dosage range and in single and repeated oral administration.
Wide inter-individual variability in the pharmacokinetic parameters has been observed. Following steady-state administration, the inter-individual variability for C_max was between 30% and 55% and for AUC was between 40% and 70%.
Ropinirole is primarily metabolized in the liver by CYP1A2. The major metabolic pathways are N-despropylation and hydroxylation to form the N-despropyl metabolite, which is the major metabolite. Animal models of dopaminergic function show that the N-despropyl metabolite is at least 100 times less potent than ropinirole. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxyl metabolites, while the hydroxy metabolite of ropinirole is rapidly glucuronidated.
Ropinirole metabolites are mainly excreted in the urine. Ropinirole is cleared from the systemic circulation with an average elimination half-life of about 6 hours (ranging from 2 to 27 hours). N-despropyl ropinirole is the predominant metabolite found in the urine (40%), followed by the carboxylic acid metabolite (10%) and the glucuronide of the hydroxyl metabolite (10%). Less than 10% of the administered dose is excreted as unchanged drug.
Special Populations: Renal impairment: There was no clinically significant change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment [creatinine clearance (CrCl) 30 to 50 mL/min].
In patients with end stage renal disease receiving regular hemodialysis, the oral clearance of ropinirole is decreased by approximately 30%. Oral clearance of the metabolites SKF-104557 and SKF-89124 were also reduced by approximately 80% and 60%, respectively.
Hepatic Impairment: The pharmacokinetics of ropinirole has not been studied in patients with hepatic impairment. Since ropinirole is extensively metabolized by the liver, higher plasma levels and lower clearance of ropinirole may be anticipated in patients with hepatic impairment.
Elderly: Compared with younger patients, the oral clearance of ropinirole is decreased by 15% in patients older than 65 years old.