ReQuip PD 24 Hour Mechanism of Action

ATC Code: N04BC04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ropinirole is a potent, non-ergoline D2/D3 dopamine agonist.
Parkinson's disease is characterised by a marked dopamine deficiency in the nigral striatal system.
Ropinirole alleviates this deficiency by stimulating striatal dopamine receptors.
Pharmacodynamic Effects: Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
Clinical Studies: A 36-week, double-blind, three-period crossover study conducted in 161 patients compared the efficacy and safety of ropinirole prolonged release tablets and ropinirole immediate release tablets as monotherapy in subjects with early phase Parkinson's disease. The primary endpoint of this non-inferiority study was the treatment difference in change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score (a 3-point non-inferiority margin was defined). Ropinirole prolonged release was demonstrated to be non-inferior to ropinirole immediate release on the primary endpoint, the adjusted mean difference between ropinirole prolonged release and ropinirole immediate release 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 indication of worsened adverse event profile and less than 3% of patients required a dose adjustment (by increasing one dose level).
A 24-week, double-blind, placebo-controlled, parallel group study evaluated the efficacy and safety of ropinirole PR as adjunctive therapy in patients with Parkinson's disease who were not optimally controlled on L-dopa. Ropinirole PR 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). The odds of ropinirole PR patients being a responder on the CGI global improvement scale were more than 4 times the odds of a placebo patient (PR 42%: IR 14%) (odds ratio 4.4 (95% CI: [2.63, 7.20]; p<0.001).
The odds of a ropinirole PR patient being a responder on the composite endpoint of 20% reduction from baseline in both L-dopa dose and "off" time were also more than 4 times that of a placebo patient (PR 54%: IR 20%) (odds ratio 4.3 (95% CI: [2.73, 6.78]; p<0.001) while the odds of a ropinirole PR patient requiring reinstatement of L-dopa following a dose reduction were 5 times lower than a placebo patient (PR 7%: IR 28%) (odds ratio 0.2 (95% CI: [0.09, 0.34]; p<0.001).
The results on the primary endpoint were supported by clinically meaningful and statistically significant superiority over placebo on secondary efficacy parameters of 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.
At week 24 the mean dose of investigational product was 18.8 mg/day for ropinirole PR and 20.0 mg/day of placebo equivalent.
Pharmacokinetics: The pharmacokinetics of ropinirole are consistent between healthy volunteers, Parkinson's disease patients and patients with Restless Legs Syndrome.
Wide inter-individual variability in the pharmacokinetic parameters has been seen. Bioavailability of ropinirole is approximately 50% (36 to 57%).
Absorption: Following oral administration of ropinirole PR, plasma concentrations increase slowly, with a median time to C_max of 6 hours. In a steady-state study in Parkinson’s disease patients receiving 12 mg of ropinirole PR 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, in the studies that established the safety and efficacy of ropinirole PR, patients were instructed to take study medication without regard to food intake.
Distribution: Plasma protein binding of the drug is low (10 to 40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 L/kg).
Metabolism: 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.
Special Patient Populations: Elderly: Oral clearance of ropinirole is reduced 15% in elderly patients (above 65 years) compared to younger patients. Dosing adjustment is not necessary in the elderly.
Renal Impairment: There was no change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with moderate renal impairment.
In patients with end stage renal disease receiving regular dialysis, oral clearance of ropinirole is reduced by approximately 30%. The recommended maximum dose is limited to 18 mg/day in patients with Parkinson’s disease (see Renal Impairment in Dosage & Administration).
Pregnancy: Physiological changes in pregnancy (including decreased CYP1A2 activity) are predicted to gradually lead to an increased maternal systemic exposure of ropinirole (reaching an approximate 2-fold increase by the third trimester based on physiologically based pharmacokinetic modelling).
Toxicology: Non-clinical Information: Carcinogenesis, Mutagenesis: Two-year studies have been conducted in the mouse and rat at dosages up to 50 mg/kg. The mouse study did not reveal any carcinogenic effect. In the rat, the only drug-related lesions were Leydig cell hyperplasia/adenoma in the testis 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. Genotoxicity was not observed in a battery of in vitro and in vivo tests.
Reproductive Toxicology: In fertility studies in rats, effects were seen on implantation due to the prolactin-lowering effect of ropinirole. In humans, chorionic gonadotropin, not prolactin, is essential for implantation in females. No effects were seen on male fertility.
Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg, increased foetal death at 90 mg/kg and digit malformations at 150 mg/kg (3.4, 5.1 and 8.5 times the mean human AUC at the Maximum Recommended Human Dose (MRHD)). There was no teratogenic effect in the rat at 120 mg/kg (6.8 times the mean human 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) administered to rabbits in combination with oral L-dopa produced a higher incidence and severity of digit malformations than L-dopa alone.
Ropinirole-related material was shown to transfer into the milk of lactating rats in small amounts (approximately 0.01% of the dose per pup).
Animal Toxicology and/or Pharmacology: Ropinirole caused no serious or irreversible toxicity in laboratory animals at 15 mg/kg (monkey), 20 mg/kg (mouse) or 50 mg/kg (rat); 0.9, 0.4 and 2.8 times the mean human AUC at the MRHD. The toxicology profile is principally determined by the pharmacological activity of the drug (behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation).