Pharmacokinetic-Pharmacodynamic Relationship of Levodopa with and without Tolcapone in Patients with Parkinson’s Disease

Objective: To investigate the effect of administration of the catechol-O-methyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson’s disease and on-off fluctuations.

Methods: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURS∑)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1: 4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100mg 3 times daily for 7 days.

Results: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUC_τ)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (C_max) increased by 1.1- to 2.1-fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURS∑ averaged 40 ± 10 points. After the first levodopa dose, CURS∑ declined to 20 ± 9 points. At day 8, the predose CURS∑ decreased to a final score of 31 ±13 points, and the maximal decline after the first levodopa dose was to a final score of 16 ± 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal E_max model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC₅₀) of levodopa was 1350 μg/L with an standard error of the population parameter estimate of 18%; adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa responsiveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8.

Conclusions: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC₅₀ of levodopa.