Brief Report A Randomized, Double-Blind Study of a Skin Patch of a Dopaminergic Agonist, Piribedil, in Parkinson’s Disease *Jean-Louis Montastruc, MD, PhD, ²Marc Ziegler, MD, *Olivier Rascol, MD, PhD, and ‡Muriel Malbezin, MD, on Behalf of the Study Group *Service de Pharmacologie Clinique, Faculte ´ de Me ´decine, Ho ˆpitaux de Toulouse, Toulouse, France; ²Unite ´ James Parkinson, Ho ˆpital Le ´opold Bellan, Paris, France; and ‡Centre d’Investigation Clinique (CIC) du Centre Hospitalier Universitaire de Toulouse, Toulouse, France Summary: This randomized, double-blind trial was designed to evaluate the efficacy of a transdermal system of piribedil on the motor symptoms of Parkinson’s disease during 3 weeks of treatment administered to three different groups: placebo, one piribedil patch (1 PP), and two (2 PP) piribedil patches. Twenty-seven patients with idiopathic Parkinson’s disease, treated with L-dopa but not sufficiently controlled, were in- cluded in this trial. The test treatment did not demonstrate any clinical efficacy on either the main end point (Unified Parkin- son’s Disease Rating Scale motor score) or the secondary end points (rigidity, bradykinesia, postural, and resting tremor scores). The main adverse events were nausea (11%), vomiting (7.4%), and malaise (7.4%) mainly observed in the placebo group (four of seven patients). The local acceptability of the transdermal system was good. Plasma piribedil concentrations at the end of treatment were 6.74 ± 1.10 and 9.31 ± 3.33 ng/mL in the 1 PP and 2 PP groups, respectively. These plasma levels could account for the lack of clinical efficacy, because a pre- vious pharmacokinetics-PD study conducted in parkinsonian patients and treated with the intravenous route demonstrated that the critical limits of activity on tremor were between 10 and 30 ng/mL. Key Words: Piribedil—Parkinson’s disease— Transdermal patch. The motor symptoms of Parkinson’s disease are mainly explained by dopaminergic nigrostriatal neuron degeneration. 1 L-dopa is converted to dopamine and is thus effective in treating the motor symptoms of Parkin- son’s disease. Although recognized as the standard therapy, its long-term use is often associated with side effects such as fluctuation of activity, dyskinesia, and psychiatric symptoms. 2,3 Dopaminergic agonists such as bromocriptine, 4 lisuride, 5,6 pergolide, 7,8 and apomor- phine 9 also act on the motor deficits of parkinsonian patients. Although not as effective as L-dopa, they have the advantage of fewer side effects. These drugs stimu- late central dopaminergic D2 receptors. Some also stimu- late D1 receptors. 10 Piribedil is a dopaminergic agonist active on all cen- tral (nigrostriatal, mesocortical, tubero-infundibular, and mesolimbic) dopaminergic pathways. 11,12 It acts essen- tially by stimulating post-synaptic D2 receptors. Animal pharmacology studies demonstrated activity in both psy- chopharmacologic tests and models predictive of Parkin- son’s disease. 13 In particular, in the marmoset monkey, piribedil is able to improve the signs induced by the neurotoxin MPTP (1 methyl-4-phenyl-1,2,3,6 tetrahy- dropyridine). 14 Clinical studies with piribedil adminis- tered orally 15 or intravenously 16 have validated its activ- ity on parkinsonian symptoms. However, after oral dos- ing, the drug undergoes a major hepatic first-pass effect. Bioavailability is consequently low, less than 10%. 17 To minimize the hepatic first-pass effect and achieve stable effective plasma concentrations, a 50-mg transdermal patch formulation was developed. Received March 13, 1998; revision received August 4, 1998. Ac- cepted October 16, 1998. Address correspondence and reprint requests to Jean-Louis Montastruc, MD, PhD, Service de Pharmacologie Clinique, Faculte ´ de Me ´decine, Ho ˆpitaux de Toulouse, 37 alle ´es Jules Guesde, 31073 Tou- louse cedex, France. Movement Disorders Vol. 14, No. 2, 1999, pp. 336–341 © 1999 Movement Disorder Society 336