Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[F-18]levodopa positron emission tomography in patients with Parkinson's disease

Objective: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic de ficit in patients with Parkinson's disease. The aim of this study was to co rrelate such parameters with positron emission tomography (PET) with levodo pa tagged with 6-fluorine 18, an established imaging method for striatal do paminergic neurons. Methods. Twenty-three patients in different disease stages (Hoehm. and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and morta lity. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK -PD modeling followed a single oral dose of levodopa/benserazide. The sum s core of the Columbia Rating Scale (CURS Sigma) was used for clinical assess ments. A nonparametric effect compartment approach assuming a sigmoidal E-m ax model was applied to the PK-PD analysis of plasma levodopa concentration s and corresponding CURS Sigma. Thereafter 6-[F-18]levodopa PET was perform ed, and the influx rate constants (k(c)) for the putamen and the caudatus r egion were correlated with the median effective concentration (EC50) and th e equilibrium half-life (T-eq) of the PK-PD model. Results: (1) A significant correlation was observed between PK-PD parameter s or with k(c) putamen as the dependent variable and the duration of the di sease as the independent variable, which explains 33% of the variability of the EC50, 42% of the variability of T-eq, and 36% of the variability of k( c). (2) Significant correlations were observed between k(c) and either EC50 or T-eq, yielding the closest correlation for the putamen region (r = -0.4 7, P < .05; and r = 0.55, P < .01; respectively). Conclusions: Our findings show that key parameters of a PK-PD model of levo dopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[F-18]levodopa PET. However, although PK-PD modeling of levodopa has bee n proven as a useful investigation of approaches aimed to restore dopaminer gic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neuro ns.