STEPWISE INTRAVENOUS-INFUSION OF APOMORPHINE TO DETERMINE THE THERAPEUTIC WINDOW IN PATIENTS WITH PARKINSONS-DISEASE

A new experimental strategy was applied to determine the concentration effect relation and the therapeutic window of apomorphine in individu al patients with Parkinson's disease. Apomorphine was administered by a stepwise intravenous infusion. The infusion rate was increased by 10 mu g/kg/h every 20 minutes, up to 100 mu g/kg/h or less when adverse effects occurred. Thereafter, the infusion rate was decreased in a ste pwise fashion until zero. Plasma apomorphine concentrations were measu red every 20 minutes. Clinical efficacy (tapping score and tremor), dy skinesia, and adverse effects were monitored at the same time. The mea n clearance of apomorphine was 4.5 L/min (2.2 to 6.6 L/min). Of the 10 patients, 8 responded to apomorphine. The effects were quantal rather than continuous. Within each patient, the concentrations at onset and offset of effect generally were similar. Significant interpatient var iability was observed with respect to minimal concentration for each o f the effects. Clinical efficacy occurred at a mean minimal effective concentration (MEC) of 4.7 ng/mL (range 1.4 to 10.7 ng/mL). Dyskinesia was observed at a mean concentration of 8.5 ng/mL (range 2.7 to 20 ng /mL). This value was not significantly different from the MEG. The mea n minimal toxic concentration was 16.7 ng/mL (8.5 to 24.5 ng/mL) and w as significantly different from the mean MEG. In conclusion, the stepw ise increase and decrease of the intravenous infusion rate is a suitab le tool for the establishment of the concentration-effect relation of apomorphine in individual patients. The finding of a narrow therapeuti c window, in which the onset concentrations vary from patient to patie nt, underlines the need for accurate and individualized dosing.