Ropinirole

The Parkinson's-Reversing Breakthrough

Parkinson Disease Treaments

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Ropinirole was approved in the United States in 1998. This dopamine agonist is a non-ergot compound with affinity for the D2 family of receptors, but not the D1 or D5 receptors. In addition, unlike pergolide or pramipexole, ropinirole lacks affinity for adrenergic, cholinergic, or serotonergic receptors (Table 1). This drug is also rapidly absorbed from the gut with peak plasma concentrations occurring in one to two hours and 40% remaining protein bound (1). The elimination half-life is six hours. The P450 CYP1A2 hepatic enzyme pathway metabolizes the drug. Ropinirole is available in 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, and 5.0 mg tablets, and is initially titrated to 9 mg/d in three divided doses over an eight-week period. Clinical improvement is usually not seen until patients are taking at least 6 mg/d. Due to the longer dosing range, up to 24 mg/d, this agent is often prescribed at subtherapeutic doses (Table 2) (15). The common side effects are similar to those seen with the other dopamine agonists, including nausea, somnolence, hallucinations, and orthostatic hypotension (Table 2) (40).

Ropinirole has been evaluated in early and advanced PD. Adler et al. (41) randomized 241 de novo subjects to ropinirole (n = 116) or placebo (n = 125) in a 24-week trial. Responders were defined as subjects achieving at least a 30% improvement in UPDRS total and motor scores. In addition, subjects were assessed for time to lev-odopa initiation by a clinical global improvement scale. With an average dosage of 15.7 mg/d, 47% of ropinirole subjects were identified as responders, whereas only 20% of subjects responded in the placebo arm. The mean changes in UPDRS scores were significant with a 24% improvement in the ropinirole group and 3% with placebo. Time to levodopa initiation significantly differed with 11% of ropinirole subjects and 29% of placebo subjects, requiring additional therapy. Requirement for levodopa therapy for the ropinirole subjects was 16%, 27%, and 40% at one, two, and three years, respectively (41).

A five-year clinical trial randomized 268 subjects to ropinirole (n = 179) or levodopa (n = 89) in a 2:1 fashion, allowing add-on levodopa at the discretion of the investigator (ropinirole 056 study) (42). In this study, 85 subjects in the ropinirole group (47%) and 45 subjects in the levodopa group (51%) completed the study. In the ropinirole group, 29 of the 85 subjects (34%) had not received levodopa supplementation at five years. The analysis of the time to dyskinesia showed a significant difference in favor of ropinirole and, at five years, the cumulative incidence of dyskinesia, regardless of levodopa supplementation, was 20% in the ropinirole group and 45% in the levodopa group. The mean daily dose of ropinirole at the end of the study was 16.5 mg/d. The average dosage for levodopa supplementation was 427 mg/d. The subjects randomized to levodopa received an average of 753 mg/d.

The results of a PET analysis comparing ropinirole to levodopa have been reported (REAL-PET) (3). This two-year randomized trial found a significant difference in striatal uptake, comparing ropinirole to levodopa in 186 subjects. Of these subjects, 162 had abnormal baseline 18F-dopa PET scans (ropinirole n = 87; levodopa n = 75). There was a 75% completion rate for each group. The mean dosage in the ropinirole group was 12.2 mg/d and in the levodopa group 559 mg/d. Fifteen out of the 87 subjects taking ropinirole needed levodopa supplementation some time during the two-year trial. Subjects in the ropinirole group had a slower decline in putamenal F-dopa uptake Ki compared to the levodopa group [- 14.1% (n = 68) vs. - 22.9% (n = 59); P < 0.001]. Subjects in the ropinirole group worsened by 0.70 points on the UPDRS motor scale from baseline, compared to an improvement of 5.64 points in the levodopa group. The ropinirole group also had dyskinesia at a significantly decreased rate when compared to the levodopa group after two years (3.4% vs. 26.7%; P < 0.001).

Lang et al. reviewed ropinirole data to assess the risk of the development of dyskinesia in subjects exposed to early dopamine agonist monotherapy. They found that once levodopa was initiated, the time to the development of dyskinesia was similar, regardless of whether levodopa was preceded by a dopamine agonist (43).

A six-month, placebo-controlled trial of 149 PD subjects with motor fluctuations randomized to ropinirole (n = 95) or placebo (n = 54) examined the reduction in levodopa and off time. In this study, levodopa dosage was reduced on an average of 31% in ropinirole subjects compared to 6% in placebo subjects. Off time was reduced by 12% in the ropinirole group and 5% in the placebo group, which was a decrease in off time of slightly more than 1 hr/day (40).

A 24-hour prolonged release formulation of ropinirole has been developed to allow for once per day dosing—an easier and more rapid titration schedule than immediate release ropinirole. A six-month, double-blind, placebo-controlled study of 393 PD subjects not optimally controlled with levodopa reported a significant decrease in daily off time of 2.1 hours with ropinirole 24-hour prolonged release, compared to a decrease of 0.3 hours in the placebo group. There were also significant improvements with ropinirole prolonged release in daily on time, on time without troublesome dyskinesia, and UPDRS ADL and motor scores, compared to placebo. Adverse events were as expected for a dopamine agonist, including dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension (44).

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