Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.           Pharmacodynamic properties

Pharmacotherapeutic group: Dopamine agonist, ATC code: N04BC04.
Mechanism of action

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.

Clinical efficacy
A 36-week, double-blind, three-period crossover study, in monotherapy, conducted in 161 patients with early phase Parkinson’s disease demonstrated that Requip Modutab prolonged-release tablets were non-inferior to Requip film-coated (immediate-release) tablets on the primary endpoint, the treatment difference in change from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (a 3-point non-inferiority margin on the UPDRS motor score was defined). The adjusted mean difference between Requip Modutab prolonged-release tablets and Requip film-coated (immediate-release) tablets at study-endpoint was 0.7 points (95% CI: [-1.51, 0.10], p=0.0842).

Following the overnight switch to a similar dose of the alternative tablet formulation, there was no difference in the adverse event profile and less than 3% of patients required a dose adjustment (all dose adjustments were increases by one dose level. No patients required a dose decrease).

A 24-week, double-blind, placebo-controlled, parallel group study of Requip Modutab prolonged-release tablets in patients with Parkinson’s disease who were not optimally controlled on levodopa demonstrated a clinically relevant and statistically significant superiority over placebo on the primary endpoint, change from baseline in awake time “off” (adjusted mean treatment difference -1.7 hours (95% CI: [-2.34, -1.09], p<0.0001). This was supported by secondary efficacy parameters of change from baseline in total awake time “on” (+1.7 hours (95% CI: [1.06, 2.33]), p<0.0001) and total awake time “on” without troublesome dyskinesias (+1.5 hours (95% CI: [0.85, 2.13]), p<0.0001). Importantly, there was no indication of an increase from baseline in awake time “on” with troublesome dyskinesias, either from diary card data or from the UPDRS items.

Study of the effect of ropinirole on cardiac repolarisation

A thorough QT study conducted in male and female healthy volunteers who received doses of 0.5, 1, 2 and 4 mg of ropinirole film-coated (immediate release) tablets once daily showed a maximum increase of the QT interval duration at the 1 mg dose of 3.46 milliseconds (point estimate) as compared to placebo. The upper bound of the one sided 95% confidence interval for the largest mean effect was less than 7.5 milliseconds. The effect of ropinirole at higher doses has not been systematically evaluated.
The available clinical data from a thorough QT study do not indicate a risk of QT prolongation at doses of ropinirole up to 4 mg/day. A risk of QT prolongation cannot be excluded as a thorough QT study at doses up to 24 mg/day has not been conducted.

Pharmacokinetic Properties

5.2.           Pharmacokinetic properties

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 Cmax 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 Cmax. Tmax was delayed by 3.0 hours.

However, in the studies that established the safety and efficacy of Requip Modutab, patients were instructed to take study medication without regard to food intake.

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 (approx. 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 (Cmax 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 Cmax 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 (see section 4.2).

Pregnancy

Physiological changes in pregnancy (including decreased CYP1A2 activity) are predicted to gradually lead to an increased maternal systemic exposure of ropinirole (see also section 4.6).