Eleven parkinsonian patients participated in a pharmacokinetic/pharmacodynamic study in an attempt to model levodopa (L-DOPA) plasma concentrations to clinical effect. Carbidopa 25 mg/L-DOPA 100 mg (Sinemet 25/100) was given orally, and blood samples were obtained before and serially for 4 hours after the dose. Effect measurements were obtained with each blood sample and included tapping score, timed walking, and global assessment of motor function. Mean L-DOPA plasma concentrations were fitted to a one-compartment pharmacokinetic model. A time-wise plot of modeled plasma L-DOPA concentrations versus mean effect measurements revealed a counter-clockwise hysteresis. Effect compartment concentrations were determined by a least squares approach, which determined elimination rate constants by minimizing hysteresis. Half-times for the equilibration between plasma and the effect compartment were 0.39 h for tapping, 0.36 h for walking, and 0.34 h for the global score. Pharmacodynamic data were fit best with an Emax model with baseline effect for tapping (Emax = 53.2 taps/60 s, EC50 = 0.58 microgram/ml) and global score (Emax set at 5.0 by limits of scale, EC50 = 2.53 micrograms/ml). A linear model best described the relationship between predicted effect site concentration and timed walking. L-DOPA plasma concentrations after oral Sinemet did not correlate well with clinical response because clinical response lags behind plasma concentrations. Half-times for equilibration between plasma and the effect site were similar for all of the effects measured.
No takes yet. Share an insight, caveat, or question.
Nelson et al. (1989) studied this question.