Clinical studies with transdermal rotigotine in early Parkinson’s disease

Abstract

After more than 30 years of clinical use, levodopa remains the gold standard of symptomatic efficacy in treating the motor deficits of Parkinson’s disease (PD). However, long-term use of levodopa is associated with disabling motor complications, including oscillations of motor response and drug-induced involuntary movements. In clinical trials and community-based studies alike, 30–40% of patients experience some type of levodopa-related motor problems after 2 to 5 years of sustained therapy.1–4 The short half-life of levodopa, combined with erratic gastrointestinal absorption, leads to fluctuating plasma levels which, in turn, are responsible for discontinuous and pulsatile stimulation of striatal dopamine (DA) receptors. Pulsatile dopaminergic stimulation is associated with a number of neuroplastic changes of striatal output neurons, which are believed to play a key role in the development of levodopa-related long-term complications, particularly the priming of the striatum to produce dyskinesias in response to levodopa.5,6 Therefore, dopaminergic agents with longer half-lives have been developed with the aim of preventing and treating levodopa-induced motor complications. Early treatment with DA agonists has been shown to produce significantly fewer motor complications over the long term, compared to levodopa, in randomized controlled trials.2,3,7,8 Alternative routes of delivery, such as IV or intraintestinal infusions of levodopa, or SC infusions of lisuride or apomorphine, can produce relatively constant levels of dopaminergic stimulation, and such treatment has been shown to reduce motor fluctuations and also to reverse pre-existing levodopa-induced dyskinesias.9–11 Continuous noninvasive dopaminergic stimulation has not been available to date. Transdermal drug delivery might fill this void. However, levodopa and many DA agonists are not sufficiently soluble to be administered via the transdermal route, and previous trials of transdermal drug delivery in PD have been unsuccessful.12,13 Rotigotine is the levorotary enantiomer of a racemic aminotetraline compound and exhibits a structure similar to that of …