Pharmacokinetic and pharmacodynamic modeling of L-dopa plasma concentrations and clinical effects in Parkinson's disease after Sinemet

• Published in: Clinical neuropharmacology Vol. 12; no. 2; p. 91
• Main Authors: Nelson, M V, Berchou, R C, Lewitt, P A, Kareti, D, Kesaree, N, Schlick, P, Galloway, M P
• Format: Journal Article
• Language: English
• Published: United States 01.04.1989
• Subjects: Adult; Aged; Carbidopa - administration & dosage; Drug Combinations - administration & dosage; Female; Humans; Levodopa - administration & dosage; Levodopa - blood; Levodopa - pharmacokinetics; Levodopa - pharmacology; Male; Mathematics; Middle Aged; Models, Theoretical; Parkinson Disease - blood; Parkinson Disease - drug therapy; Parkinson Disease - metabolism
• ISSN: 0362-5664
• DOI: 10.1097/00002826-198904000-00002

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.