Ropinirole Other names: Ropinotergotirole

Ropinirole is a non-ergoline D₂/D₃ dopamine agonist which stimulates striatal dopamine receptors.

Ropinirole alleviates the dopamine deficiency which characterises Parkinson’s disease by stimulating striatal dopamine receptors.

Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.

Absorption

Bioavailability of ropinirole is approximately 50% (36–57%). Following oral administration, of ropinirole prolonged-release tablets plasma concentrations increase slowly, with a median time to C_max generally achieved between 6 and 10 hours.

In a steady-state study in 25 Parkinson’s disease patients receiving 12 mg of ropinirole prolonged release tablets once daily, a high fat meal increased the systemic exposure to ropinirole as shown by an average 20% increase in AUC and an average 44% increase in C_max. T_max was delayed by 3.0 hours. However, these changes are unlikely to be clinically relevant (eg. increased incidence of adverse events).

The systemic exposure to ropinirole is comparable for ropinirole prolonged-release tablets and ropinirole film-coated (immediate-release) tablets based on the same daily dose.

Distribution

Plasma protein binding of Ropinirole is low (10–40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approximately 7 L/kg).

Biotransformation

Ropinirole is primarily cleared by CYP1A2 metabolism and its metabolites are mainly excreted in the urine. The major metabolite is at least 100-times less potent than ropinirole in animal models of dopaminergic function.

Elimination

Ropinirole is cleared from the systemic circulation with an average elimination half-life of about 6 hours. The increase in systemic exposure (C_max and AUC) to ropinirole is approximately proportional over the therapeutic dose range. No change in the oral clearance of ropinirole is observed following single and repeated oral administration. Wide inter-individual variability in the pharmacokinetic parameters has been observed. Following steady-state administration of ropinirole prolonged-release tablets, the inter-individual variability for C_max was between 30% and 55% and for AUC was between 40% and 70%.

Renal Impairment

There was no change observed in the pharmacokinetics of ropinirole in Parkinson’s disease patients with mild to moderate renal impairment.

In patients with end stage renal disease receiving regular haemodialysis, oral clearance of ropinirole is reduced by approximately 30%. Oral clearance of the metabolites SKF-104557 and SKF-89124 were also reduced by approximately 80% and 60% respectively. Therefore, the recommended maximum dose is limited to 18 mg/day in these patients with Parkinson’s disease.

Pregnancy

Physiological changes in pregnancy (including decreased CYP1A2 activity) are predicted to gradually lead to an increased maternal systemic exposure of ropinirole.

Reproductive Toxicity

In fertility studies in female rats, effects were seen on implantation due to the prolactin-lowering effect of ropinirole. It should be noted that prolactin is not essential for implantation in humans.

Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (mean AUC in rats approximately twice the highest AUC at the Maximum Recommended Human Dose (MRHD)), increased foetal death at 90 mg/kg/day (approximately 3 times the highest AUC at the MRHD), and digit malformations at 150 mg/kg/day (approximately 5 times the highest AUC at the MRHD). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 4 times the highest AUC at the MRHD) and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (9.5 times the mean human C_max at the MRHD). However, ropinirole at 10 mg/kg (4.8 times the mean human C_max at the MRHD) ad ministered to rabbits in combination with oral L-dopa produced a higher incidence and severity of digit malformations than L-dopa alone.

Toxicology

The toxicology profile is principally determined by the pharmacological activity of ropinirole: behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation. In the albino rat only, retinal degeneration was observed in a long term study at the highest dose (50 mg/kg/day), and was probably associated with an increased exposure to light.

Genotoxicity

Genotoxicity was not observed in the usual battery of in vitro and in vivo tests.

Carcinogenicity

From two-year studies conducted in the mouse and rat at dosages up to 50 mg/kg/day there was no evidence of any carcinogenic effect in the mouse. In the rat, the only ropinirole-related lesions were Leydig cell hyperplasia and testicular adenoma resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.

Safety Pharmacology

In vitro studies have shown that ropinirole inhibits hERG-mediated currents. The IC₅₀ is 5-fold higher than the expected maximum plasma concentration in patients treated at the highest recommended dose (24 mg/day).