Longitudinal monitoring of the levodopa concentration-effect relationship in Parkinson’s disease

We prospectively evaluated over 4 years the intrasubject relationship betweenlevodopa plasma concentration and the tapping effect after a standard oral levodopa test in28 patients with mild-to-moderate idiopathic Parkinson’s disease. The onset and duration of the tapping effect significantly shortened over years; response amplitude did notvary. Levodopa plasma kinetics remained unchanged. Pharmacodynamic modeling indicated aprogressive decrease in the equilibration half-life between plasma drug concentration andeffect, which correlated with the shorter motor response. No clear-cut change in maximum response (E_max) emerged, but levodopa concentration needed to yield 50%of maximum effect (EC₅₀) significantly increased. These data indicate thatthe duration of motor response becomes a major determinant of drug efficacy over years.The modifications in levodopa effect-compartment equilibration half-life and EC50 further support the suggestion thatalterations in cerebral levodopa kinetics have an important role in the development ofresponse fluctuations.