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-me thyltransferase (COMT) inhibitor tolcapone on the concentration-effect rela tionship of levodopa in patients with advanced Parkinson's disease and on-o ff fluctuations. Design: Nonblind single group 2-period pharmacokinetic-pharmacodynamic stud y. Patients and participants: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. Methods: The pharmacokinetics [plasma concentrations of levodopa and 3-O-me thyldopa (3-OMD)] and motor effects [global score of the Columbia Universit y Rating Scale (CURS Sigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1 :4) were determined for 4 consecutive dosage inter vals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and d uring (day 8) coadministration of tolcapone 100mg 3 times daily for 7 days. Results: Under tolcapone, exposure to levodopa [area under the plasma conce ntration-time for the dosage interval (AUC(tau))] 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 X were re duced to about 20% of the values at day 1. At baseline (day 1, before the f irst levodopa dose), CURS Sigma averaged 40 +/- 10 points. After the first levodopa dose. CURS Sigma declined to 20 +/- 9 points. At day 8, the predos e CURS Sigma decreased to a final score of 31 +/- 13 points, and the maxima l decline after the first levodopa dose was to a final score of 16 +/- 8 po ints. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage interv als did not show differences in levodopa responsiveness with or without tol capone. The population mean of the 50% effective concentration (EC50) of le vodopa was 1350 mug/L with an standard error of the population parameter es timate of 18% adding tolcapone treatment as a covariate did not significant ly change the population fit. Circadian influences on levodopa responsivene ss were not evaluable by the NONMEM model due to overparametrisation, but v isual inspection of plotted data did not suggest differences in the concent ration-effect relationship between the 4 consecutive dosage intervals on da ys 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 pat ients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-br ain barrier, which otherwise would have led to a decrease in the EC50 of le vodopa.