Safety of Entacapone and Apomorphine Coadministration in Levodopa-Treated Parkinson’s Disease Patients: Pharmacokinetic and Pharmacodynamic Results of a Multicenter, Double-Blind, Placebo-Controlled, Cross-Over Study Jan C.M. Zijlmans, MD, PhD, 1–3 Berengere Debilly, MD, 4 Olivier Rascol, MD, PhD, 5 Andrew J. Lees, MD, FRCP, 1,2 and Franck Durif, MD, PhD 4 * 1 National Hospital for Neurology and Neurosurgery, London, United Kingdom 2 Reta Lila Weston Institute of Neurological Studies, University College London, United Kingdom 3 Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands 4 Federation de Neurologie, Hopital Gabriel Montpied, Clermont Ferrand, France 5 Clinical Investigation Centre, Department of Clinical Pharmacology, INSERM U 455, Toulouse University Hospital, France Abstract: We investigated whether administration of the cat- echol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson’s disease patients experiencing se- vere motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three- sequence, three-period, crossover design. Patients were ran- domly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at base- line and study end. Pharmacokinetic parameters for apomor- phine (C max , AUC, t max ,t 1/2 ) were unchanged by the adminis- tration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkin- son’s disease. © 2004 Movement Disorder Society Key words: levodopa; apomorphine; entacapone; Parkin- son’s disease; pharmacokinetics The symptoms of Parkinson’s disease (PD) can be- come increasingly difficult to control as the disease ad- vances, particularly with the development of motor com- plications that often emerge after long-term levodopa therapy. 1,2 In cases with on– off fluctuations, apomor- phine, a mixed dopamine agonist, is frequently used as a “rescue” adjunct to levodopa (L-dopa) as it induces an on state within 10 to 15 minutes of administration. 3–5 Before these debilitating on– off fluctuations emerge, the majority of patients will have already developed the symptoms of “wearing-off,” where the therapeutic ben- efit of each L-dopa dose lasts for increasingly shorter periods of time. Since their introduction in the 1990s, catechol-O-methyl transferase (COMT) inhibitors such as entacapone have been increasingly used to effectively *Correspondence to: Dr. Franck Durif, Federation de Neurologie, Hopital Gabriel Montpied, Clermont Ferrand, Cedex 1, France. E-mail: fdurif@chu-clermontferrand.fr Received 17 October 2003; Accepted 1 March 2004 Published online 10 June 2004 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.20188 Movement Disorders Vol. 19, No. 9, 2004, pp. 1006 –1011 © 2004 Movement Disorder Society 1006