Transdermal Rotigotine for the Management of Parkinson’s Disease
Transdermal Rotigotine for the Management of Parkinson’s Disease
Rotigotine is a highly lipophilic dopamine-receptor agonist and the first transdermally delivered agent to demonstrate efficacy and safety as monotherapy in early Parkinson's disease and to reduce "off" hours in levodopa-treated patients with advanced Parkinson's disease. The rotigotine pharmacophore is nonergolinic and demonstrates high affinity for dopamine D2 and D3 receptors. With once-daily application, the patch matrix provides continuous, nonfluctuating plasma drug levels at steady state, resulting in continuous and steady plasma and brain levels and striatal dopamine-receptor stimulation. In early Parkinson's disease, doses of rotigotine up to 8 mg/24 hours demonstrate comparable efficacy to ropinirole (at doses up to 12 mg/day); in advanced Parkinson's disease, doses of rotigotine up to 16 mg/24 hours demonstrate comparable efficacy and tolerability to pramipexole (at doses up to 4.5 mg/day). In the registration trials for early and advanced Parkinson's disease, the adverse effects most commonly observed with rotigotine were minor application site reactions, dizziness, nausea, and somnolence. Doses of transdermal rotigotine can be titrated to a maintenance dose within 2–3 weeks, and the once-daily regimen minimizes complexity of therapy. The transdermal delivery system is also an advantage when nonoral administration is desired, and the 24-hour, continuous, nonfluctuating drug levels can improve early morning and nocturnal symptoms of Parkinson's disease. Thus, transdermally delivered rotigotine is a clinically innovative and useful addition to the dopamine-receptor agonist class. This review summarizes the key pharmacologic and clinical data for rotigotine and provides a focused clinical context for its use in early-to-advanced Parkinson's disease, as well as a brief summary for its role in restless legs syndrome.
Parkinson's disease is an irreversible and progressive neurodegenerative disorder that is diagnosed based on the clinical detection of slowness (bradykinesia) or paucity (akinesia) of movement along with a resting tremor and/or resistance to passive movement of the joints (rigidity). The two hallmark histopathologic features of Parkinson's disease are depigmentation of the substantia nigra pars compacta (SNc), which reflects the loss of dopamine-producing neurons, and presence of Lewy bodies or neurites (neuronal cytoplasmic filamentous aggregrates composed of the presynaptic protein α-synuclein) in the remaining SNc neurons. Based on an estimated prevalence range of 31–328/100,000 persons and the 2009 world population census, up to 22 million people have Parkinson's disease worldwide.
Mainstays of symptomatic therapies for Parkinson's disease target the dopaminergic nigrostriatal system, which is composed of fibers projecting from the SNc to the striatum (putamen and caudate). In the striatum, these fibers form synaptic connections with two populations of dopamine-receptor–mediated efferent neurons, referred to as the D1 direct and D2 indirect pathways, which in turn mediate motor activity through a complex neuronal circuit involving the extrapyramidal system. In Parkinson's disease, the degeneration of the SNc neurons results in reduced activity within these two efferent pathways, which in turn results in inhibition of thalamic activity and reduced activation of the motor cortex. Restoring activity at the D2 receptor in patients with Parkinson's disease appears to be of critical importance for mediating clinical improvements.
Abstract and Introduction
Abstract
Rotigotine is a highly lipophilic dopamine-receptor agonist and the first transdermally delivered agent to demonstrate efficacy and safety as monotherapy in early Parkinson's disease and to reduce "off" hours in levodopa-treated patients with advanced Parkinson's disease. The rotigotine pharmacophore is nonergolinic and demonstrates high affinity for dopamine D2 and D3 receptors. With once-daily application, the patch matrix provides continuous, nonfluctuating plasma drug levels at steady state, resulting in continuous and steady plasma and brain levels and striatal dopamine-receptor stimulation. In early Parkinson's disease, doses of rotigotine up to 8 mg/24 hours demonstrate comparable efficacy to ropinirole (at doses up to 12 mg/day); in advanced Parkinson's disease, doses of rotigotine up to 16 mg/24 hours demonstrate comparable efficacy and tolerability to pramipexole (at doses up to 4.5 mg/day). In the registration trials for early and advanced Parkinson's disease, the adverse effects most commonly observed with rotigotine were minor application site reactions, dizziness, nausea, and somnolence. Doses of transdermal rotigotine can be titrated to a maintenance dose within 2–3 weeks, and the once-daily regimen minimizes complexity of therapy. The transdermal delivery system is also an advantage when nonoral administration is desired, and the 24-hour, continuous, nonfluctuating drug levels can improve early morning and nocturnal symptoms of Parkinson's disease. Thus, transdermally delivered rotigotine is a clinically innovative and useful addition to the dopamine-receptor agonist class. This review summarizes the key pharmacologic and clinical data for rotigotine and provides a focused clinical context for its use in early-to-advanced Parkinson's disease, as well as a brief summary for its role in restless legs syndrome.
Introduction
Parkinson's disease is an irreversible and progressive neurodegenerative disorder that is diagnosed based on the clinical detection of slowness (bradykinesia) or paucity (akinesia) of movement along with a resting tremor and/or resistance to passive movement of the joints (rigidity). The two hallmark histopathologic features of Parkinson's disease are depigmentation of the substantia nigra pars compacta (SNc), which reflects the loss of dopamine-producing neurons, and presence of Lewy bodies or neurites (neuronal cytoplasmic filamentous aggregrates composed of the presynaptic protein α-synuclein) in the remaining SNc neurons. Based on an estimated prevalence range of 31–328/100,000 persons and the 2009 world population census, up to 22 million people have Parkinson's disease worldwide.
Mainstays of symptomatic therapies for Parkinson's disease target the dopaminergic nigrostriatal system, which is composed of fibers projecting from the SNc to the striatum (putamen and caudate). In the striatum, these fibers form synaptic connections with two populations of dopamine-receptor–mediated efferent neurons, referred to as the D1 direct and D2 indirect pathways, which in turn mediate motor activity through a complex neuronal circuit involving the extrapyramidal system. In Parkinson's disease, the degeneration of the SNc neurons results in reduced activity within these two efferent pathways, which in turn results in inhibition of thalamic activity and reduced activation of the motor cortex. Restoring activity at the D2 receptor in patients with Parkinson's disease appears to be of critical importance for mediating clinical improvements.
