S Harder1, H Baas. 1. Institute for Clinical Pharmacology and the Clinic for Neurology, University Hospital Frankfurt am Main, Frankfurt, Germany.
Abstract
OBJECTIVE: To assess differences in the pharmacokinetic and pharmacodynamic relations of levodopa in clinically defined groups and to prove that pharmacokinetic and pharmacodynamic parameters are associated with duration of disease and length of treatment. METHODS: We studied the pharmacokinetic and pharmacodynamic relations of levodopa after a single dose (100 mg levodopa with 25 mg benserazide) among four groups of patients with Parkinson's disease. Group 1 was levodopa-naive patients (n = 8); group 2 was patients in stable condition taking levodopa (n = 10); group 3 was patients with on-and-off fluctuations (n = 11); and group 4 was patients with on-and-off fluctuations and peak-dose dyskinesia (n = 8). The Columbia University Rating Scale was used for clinical assessment. The pharmacokinetic-pharmacodynamic analysis was based on an estimate of the maximal response model with a semiparametric approach to effect-site equilibrium (equilibration half-life). RESULTS: The mean concentration at half-maximal effect estimated for the different groups was as follows (mean value +/- SD): group 1, 389 +/- 138 ng x ml(-1); group 2, 346 +/- 203 ng x ml(-1); group 3, 543 +/- 245 ng x ml(-1); group 4, 711 +/- 215 ng x ml(-1). Estimate of the maximal response was determined to be the following: group 1, 10 +/- 3; group 2, 12 +/- 5; group 3, 24 +/- 13; group 4, 18 +/- 7. A significant correlation was observed between duration of Parkinson's disease and mean concentration at half-maximal effect (p < 0.001), estimate of maximal response (p < 0.05), and, inversely, equilibration half-life (p < 0.05). CONCLUSIONS: The data suggested that levodopa-naive patients and patients in stable condition taking levodopa do not differ in pharmacokinetic-pharmacodynamic relations, whereas patients with fluctuations, especially patients with peak-dose dyskinesia, exhibit a larger threshold level (mean concentration at half-maximal effect). It was concluded that progression of the disease (loss of endogenous dopamine synthesis and reduced dopamine storage) is reflected by pharmacokinetic and pharmacodynamic parameters that characterize the demand for exogenous dopamine provided by levodopa.
OBJECTIVE: To assess differences in the pharmacokinetic and pharmacodynamic relations of levodopa in clinically defined groups and to prove that pharmacokinetic and pharmacodynamic parameters are associated with duration of disease and length of treatment. METHODS: We studied the pharmacokinetic and pharmacodynamic relations of levodopa after a single dose (100 mg levodopa with 25 mg benserazide) among four groups of patients with Parkinson's disease. Group 1 was levodopa-naive patients (n = 8); group 2 was patients in stable condition taking levodopa (n = 10); group 3 was patients with on-and-off fluctuations (n = 11); and group 4 was patients with on-and-off fluctuations and peak-dose dyskinesia (n = 8). The Columbia University Rating Scale was used for clinical assessment. The pharmacokinetic-pharmacodynamic analysis was based on an estimate of the maximal response model with a semiparametric approach to effect-site equilibrium (equilibration half-life). RESULTS: The mean concentration at half-maximal effect estimated for the different groups was as follows (mean value +/- SD): group 1, 389 +/- 138 ng x ml(-1); group 2, 346 +/- 203 ng x ml(-1); group 3, 543 +/- 245 ng x ml(-1); group 4, 711 +/- 215 ng x ml(-1). Estimate of the maximal response was determined to be the following: group 1, 10 +/- 3; group 2, 12 +/- 5; group 3, 24 +/- 13; group 4, 18 +/- 7. A significant correlation was observed between duration of Parkinson's disease and mean concentration at half-maximal effect (p < 0.001), estimate of maximal response (p < 0.05), and, inversely, equilibration half-life (p < 0.05). CONCLUSIONS: The data suggested that levodopa-naive patients and patients in stable condition taking levodopa do not differ in pharmacokinetic-pharmacodynamic relations, whereas patients with fluctuations, especially patients with peak-dose dyskinesia, exhibit a larger threshold level (mean concentration at half-maximal effect). It was concluded that progression of the disease (loss of endogenous dopamine synthesis and reduced dopamine storage) is reflected by pharmacokinetic and pharmacodynamic parameters that characterize the demand for exogenous dopamine provided by levodopa.
Authors: Chukwuemeka S Okereke; Louis Kirby; Dinesh Kumar; Edward I Cullen; Raymond D Pratt; William A Hahne Journal: Br J Clin Pharmacol Date: 2004-11 Impact factor: 4.335