DOSE-RESPONSE AND CONCENTRATION RESPONSE RELATIONSHIP OF APOMORPHINE IN PATIENTS WITH PARKINSONS-DISEASE AND END-OF-DOSE AKINESIA

The motor response and the PK-PD relationship of the dopamine agonist, apomorphine, after ascending single doses (0.5, 1, 2, 4 mg s.c.), was investigated in 10 patients with advanced Parkinson's disease present ing end-of-dose motor fluctuations. Aim of the study was to investigat e the exact pharmacodynamic effects of different apomorphine doses on the magnitude and duration of motor responses in parkinsonian fluctuat ors. The average improvement in the magnitude of the motor response (% change of baseline score in the Columbia University Rating Scale) eli cited by apomorphine was negligible with 0.5 mg, 10% after the 1 mg do se, 22% after 2 mg, and 25% after 4 mg. If a 20% improvement is consid ered clinically relevant, a response was seen in 0/10 patients (0.5 mg ), 2/10 patients (1 mg), 6/10 patients (2 mg), and 6/8 patients (4 mg) . The duration of response was about 0.25 h (1 mg), 0.58 h (2 mg), and 0.72 h (4 mg). An explorative analysis of individual plasma concentra tion vs. effect curve, yielded a steep, sigmoidal concentration effect relationship with fast equilibrium at the effect site. The EC50 of th e individual curves averaged 20 pMol/ml. However, several curves exhib ited proteresis, making the application of a PK-PD model impossible. T he reason for proteresis is not clear, it might indicate acute toleran ce as well as a redistribution of apomorphine from the effect site.