Concentration‐effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.

Abstract

1 The relationship between plasma concentration of levodopa and motor-response was investigated in 12 patients with Parkinson's disease who showed marked response fluctutations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg benserazide) and a controlled release (CR) formulation (300 mg levodopa/75 mg benserazide), using a double-blind, randomized, cross-over design. 2 The sum score of the Columbia University Rating Scale (CURSE) was used for pharmacodynamic assessment. A sigmoidal Emax-model was fitted to the data using a semiparametric pharmacokinetic/dynamic approach. 3 The dose-corrected AUC of levodopa after the IR-formulation was 27.5 (± 9.1 s.d.) ng ml-' h per mg and 23.2 (± 4.6 s.d.) ng ml-' h per mg after the CR-formulation. Cmax was 1714 (± 1027 s.d.) ng ml-' after the IR-formulation and 1494 (± 383 s.d.) ng ml-' after the CR-formulation. 4 With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS£ rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (± 144 s.d.) ng ml-' (IR) and 1024 (± 502 s.d.) ng ml-' (CR), respectively (95%-CI: 1.51-2.66, point estimator 1.95). The mean duration of the motor response was 1.9 (± 0.5 s.d.) h (IR) and 2.8 (± 0.7 s.d.) h (CR), respectively (95%-Cl: 1.12-2.04, point estimator 1.53). 5 The difference in the responsiveness after the CR-formulation might be due to the increase in the concentrations of 3-O-methyldopa which rose from 5410 (± 2360 s.d.) ng ml-' pre-dose to 6126 (± 2660 s.d.) ng ml-' post-dose after the IR-form and from 5146 (± 2292 s.d.) ng ml-' pre-dose to 6873 (± 2830 s.d.) ng ml-' postdose after the CR-form (95%-CI for the difference Cmax-Cmin: 2.04-3.88, point estimator 2.63).6 Although the peak response (i.e. Emax) was not different after the two formulations, a gain in the duration of the motor response, which might be provided by sustained plasma concentrations of levodopa after the CR-preparation was offset partially by the apparent doubling of the threshold level (EC50).

Pharmacokinetic Studies with a Dual-Release Formulation of Levodopa, a Novel Principle in the Treatment of Parkinson’s Disease

“…Maximum levodopa concentrations, however, were attained quicker in the presence than in the absence of food with mean t max values of 1.3 and 2.5 h, respectively. A shorter delay to turn to the ON-state would therefore be expected when patients take Madopar ® DR in close association with a meal [2]. However, the results of a pilot study with Madopar ® DR in 61 patients with Parkinson's disease suggested that efficacy and tolerability were not influenced by the interval between drug and meal intake [15].…”

“…Although complex in advanced stages of the disease, relationships exist between plasma levels of levodopa and clinical efficacy in patients with Parkinson's disease [2]. Immediate-release formulations of levodopa suffer from high peak levels and a short elimination half-life of only about 1 h, resulting in the need of frequent dosing [3].…”

The effect of exercise on pharmacokinetics and pharmacodynamics of levodopa

“…The equilibrium half time T eq was derived by ln (2)/k e0 and could be interpreted as a measure for the lag time between changes of drug concentration in the central compartment and changes of the drug effect. [12][13][14] Most published studies on the concentration-effect relationship of levodopa were carried out in patients with fluctuating idiopathic PD and focused on improvement of motor impairment (rigor, tremor, and akinesia) by levodopa. 12,13,15 Despite some heterogeneity in regard to the study designs (that is, different score systems for the motor response), these studies showed almost consistent findings and proved the E max model to be the most suitable to describe the concentration-effect relationship of levodopa.…”

“…[12][13][14] Most published studies on the concentration-effect relationship of levodopa were carried out in patients with fluctuating idiopathic PD and focused on improvement of motor impairment (rigor, tremor, and akinesia) by levodopa. 12,13,15 Despite some heterogeneity in regard to the study designs (that is, different score systems for the motor response), these studies showed almost consistent findings and proved the E max model to be the most suitable to describe the concentration-effect relationship of levodopa. In all studies, the steepness of the concentration-effect curves, characterized by the Hill coefficient N, was high (>5 units), indicating an almost immediate onset of motor response to levodopa when the EC 50 is reached and the appearance of off reactions when concentrations are below this level.…”

Sustained-release of levodopa: single dose study of a new formulation

“…Motor fluctuations are at least partially caused by the extreme fluctuations in levodopa plasma concentrations (Fahn, 1974;Sweet et al, 1974;Tolesa et al, 1975;Eriksson et al, 1984;Nutt et al, 1984;Poewe et al, 1986;Nutt, 1987;Mouradian and Chase, 1988;Mouradian et al, 1988a). In order to achieve constant plasma levels of levodopa this sustained-release (SR) formulations have been developed and applicated in recent years (Poewe et al, 1986;Kleedorfer and Poewe, 1992;Kurth et al, 1993;Pahwa et al, 1993;Stocchi et al, 1994;Bergemann et al, 1994;Harder et al, 1995). Beneficial effects of levodopa "slow release" treatment mainly in patients with "wearing off" fluctuations were observed, but duration of interdose dyskinesia increased.…”