PHARMACODYNAMICS OF LEVODOPA COADMINISTERED WITH APOMORPHINE IN PARKINSONIAN-PATIENTS WITH END-OF-DOSE MOTOR FLUCTUATIONS

The modification of the pharmacodynamic response to a single oral dose of levodopa/benserazide by the coadministration of the dopamine agoni st apomorphine was investigated in parkinsonian patients with end-of-d ose motor fluctuations. The relation between levodopa plasma concentra tions and motor response was examined in a double-blind, randomized, c rossover design in 10 patients with idiopathic Parkinson's disease wit h end-of-dose motor fluctuations. Oral single-dose challenges with 100 mg of levodopa/25 mg of benserazide were carried out twice in each pa tient, under coadministration with apomorphine (1 mg/h) or 0.9% saline (placebo) subcutaneously. The sum scores to score) of the Columbia Un iversity Rating Scale (CURS) were used as effect parameters for pharma codynamic assessment. A sigmoidal E-max model was fitted to the data u sing a semiparametric pharmacokinetic-pharmacodynamic approach. Levodo pa pharmacokinetics were not significantly modified by the coadministr ation of apomorphine. The area under the curve was 1599 +/- 615 ng.ml( -1)h. (levodopa + saline) and 1821 +/- 625 ng.ml(-1).h (levodopa + apo morphine). C-max was 1094 +/- 476 ng.ml(-1) (levodopa + saline) and 11 29 +/- 435 ng.ml(-1) (levodopa + apomorphine). Under both experimental regimens, the maximum clinical response to levodopa (E-max) yielded a decrease in the CURS sigma rating of about 20 score points. Estimates of the EC50 of levodopa decreased significantly from 430 +/- 163 ng.m l(-1) (levodopa + saline) to 315 +/- 123 ng+ml(-1) (levodopa + apomorp hine) (95% confidence interval [CI] 0.51 - 0.98, point estimator 0.75) . The mean duration of the motor response rose from 1.9 +/- 0.5 h (lev odopa + saline) to 3.0 +/- 0.9 h (levodopa + apomorphine (95% CI 1.23 to 2.06, point estimator 1.60). Thus, a reduction of the threshold lev els for levodopa (EC50) was accompanied by approximately 50% gain in o n-phase duration, but not in an increased magnitude of the motor respo nse (E-max).