Cabergoline

Publisher Website
Google Scholar
Abstract
Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for dopamine D2 receptors and a long elimination half-life. This agent provides continuous dopaminergic stimulation with once-daily administration. Adjuvant oral cabergoline is usually well tolerated and effective in controlling symptoms in patients with advanced Parkinson’s disease experiencing response fluctuations to long-term levodopa therapy. In patients with early Parkinson’s disease, cabergoline (with or without levodopa) is well tolerated and effective in controlling disease symptoms, and may reduce the risk of developing drug-induced motor complications. Data from two pharmacoeconomic analyses suggest that cabergoline may be a cost-effective treatment option versus levodopa in patients with early Parkinson’s disease, and highlight the need for further evaluation of the drug in this indication. Cabergoline is a dopaminergic synthetic ergoline derivative, with high and prolonged affinity for human dopamine D2 and D3 receptors, but limited affinity for D1 receptors. The drug also demonstrates some affinity for nondopaminergic (serotonergic and adrenergic) brain receptors. In animal models, cabergoline has demonstrated neuroprotective effects. In open-label trials, an evening dose of cabergoline had a beneficial effect on nocturnal motor symptoms in patients with Parkinson’s disease, with significantly reduced nocturnal akinesias and early-morning dyskinesias. The pharmacokinetic profile of oral cabergoline at steady-state is linear within the recommended dosage range, with peak plasma concentrations being reached within 0.5–3 hours. Cabergoline is extensively distributed into body tissues, including the brain. Cabergoline has a long elimination half-life (63–109 hours), allowing for convenient once-daily administration. The pharmacokinetics of cabergoline are unaffected by mild-to-moderate renal impairment, food, age or gender. There is no pharmacokinetic interaction between cabergoline and levodopa. Patients with Advanced Parkinson’s Disease Receiving Levodopa: The improvement in parkinsonian symptoms with adjuvant oral cabergoline was similar to that achieved with bromocriptine and was significantly superior to that with placebo. Efficacy was assessed according to the Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living (ADL) and motor function subscores, or percentage of patients with improvements in motor disability in the Clinical Global Impression scale. The reduction in the percentage of ‘off’ hours with adjuvant cabergoline was significantly greater than that with placebo (p < 0.05), but similar to that with bromocriptine. The daily levodopa dose required was significantly less with cabergoline than placebo (p < 0.001). Adjunctive cabergoline and pergolide both improved parkinsonian symptoms, according to the UPDRS motor performance subscale (p < 0.001 vs baseline) in a small crossover study. However, cabergoline was more effective than pergolide in controlling motor performance during the ‘off’ phase (p < 0.05). Patients with Early Parkinson’s Disease: Oral cabergoline (with or without additional levodopa) was as effective as levodopa alone in improving the symptoms of Parkinson’s disease during the first year of treatment, with a >30% decrease versus baseline in UPDRS motor function subscore occurring in 81% versus 87% of patients, respectively. With long-term treatment, there was a gradual decrease in the improvement in UPDRS motor function subscores in both treatment groups. Similarly, UPDRS ADL subscores improved significantly from baseline in both treatment groups in the first year of therapy, with a subsequent decline in the rate of improvement thereafter. Motor complications developed in significantly fewer patients after long-term treatment with cabergoline (with or without additional levodopa) than with levodopa alone (22% vs 34%; p < 0.05). In patients who remained on cabergoline or levodopa monotherapy, the respective incidence of motor complications was 5.3% versus 15.5% (p-value not stated). Cabergoline was considered cost effective in patients with newly diagnosed Parkinson’s disease, based on the incremental costs per benefit gained versus levodopa. Analyses were decision-analysis (Markov) models and were based on data from a 5-year clinical study. From a German societal perspective, the incremental cost (direct and indirect) of cabergoline monotherapy versus levodopa over a 10-year period was €1031 per decreased UPDRS score point for patients aged ≥60 years (year 2002 values). Over a 5-year period, and from a Swedish public healthcare system perspective, cabergoline (with or without additional levodopa) was associated with incremental costs (direct) of €13 863 per year of motor complications avoided versus levodopa (year 2000 values). Cabergoline 0.5-6 mg/day was generally well tolerated, with adverse events usually being transient and mild to moderate in severity. In patients with advanced Parkinson’s disease receiving levodopa, the incidence of adverse events with the addition of cabergoline (74%) was similar to that with placebo (68%). In patients with newly diagnosed Parkinson’s disease, the incidence of adverse events associated with cabergoline (with or without levodopa) was similar to that with levodopa alone (83% and 82%). Common adverse events associated with cabergoline in clinical trials in patients receiving levodopa included CNS disturbances (dyskinesia, hyperkinesia, hallucinations, confusion), gastrointestinal disturbances (nausea, vomiting, dyspepsia, gastritis) and cardiovascular events (postural hypotension, dizziness and peripheral oedema). The incidence of cardiopulmonary fibrosis in non-susceptible individuals treated with cabergoline is low (<2%). Cabergoline (with or without levodopa) has been associated with somnolence, although excessive daytime somnolence and sudden sleep onset episodes (‘sleep attacks’) are rare. In a small open-label study in nine patients with early Parkinson’s disease, switching from monotherapy with alternative dopamine agonists to cabergoline monotherapy (administered at bedtime) resulted in a reduction in daytime sleepiness.