Pharmacodynamic modeling of oral levodopa: clinical application in Parkinson's disease.
We investigated the relationship between levodopa plasma concentration and the tapping effect, after a standard oral levodopa test, by kinetic-dynamic modeling in 40 parkinsonian patients with stable or fluctuating response to levodopa, and found no difference in levodopa plasma pharmacokinetics between stable and fluctuating patients. Conversely, levodopa equilibration half-life between plasma and effect-site concentration was five-fold shorter on average in fluctuating patients. Overall, levodopa equilibration half-life highly correlated with the duration of tapping response and provided a reliable quantitative index of central mechanisms that affect the length of clinical effect. Individual fitting of tapping measures to modeled drug effect-site concentrations by sigmoid Emax model revealed that fluctuating patients required almost two-fold higher levodopa concentrations (EC50) to elicit almost the same motor response (Emax). These findings suggest that shortening of levodopa clinical effect may be accompanied by a reduced drug affinity for the nigrostriatal dopaminergic system (EC50), with no change in its intrinsic activity (Emax).
Contin
M
M
Institute of Neurology, University of Bologna, Italy.
Riva
R
R
Martinelli
P
P
Cortelli
P
P
Albani
F
F
Baruzzi
A
A
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010300:Parkinson Disease / Q000188:drug therapy*
D007980:Levodopa