Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2000) 67, 610–620; doi: 10.1067/mcp.2000.106795
Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone
Karin Jorga PhD1, Ludger Banken PhD1, Bärbel Fotteler MSc1, Paul Snell PhD1 and Jean-Louis Steimer PhD1
1Department of Research and Development, F. Hoffmann– La Roche Ltd, Basel, Switzerland.
Correspondence: Karin Jorga, PhD, Department of Clinical Pharmacology, F. Hoffmann–La Roche, CH-4070 Basel, Switzerland. E-mail: karin.jorga@roche.com
Received 27 October 1999; Accepted 26 February 2000.
Abstract
Objective: To use pharmacostatistical models to evaluate the overall exposure of patients with Parkinson's disease to levodopa in the presence and absence of tolcapone.
Methods: Four hundred twelve patients with Parkinson's disease with fluctuating and nonfluctuating responses to levodopa participated in three multicentered, parallel, double-blind, placebo-controlled dose-finding studies and received either placebo or tolcapone in addition to levodopa-decarboxylase inhibitor therapy. Sparse blood samples were obtained from 393 patients for levodopa and 3-O-methyldopa assay, and the data were analyzed with use of the NONMEM program.
Results: The fraction of levodopa metabolized to 3-O-methyldopa was substantially reduced by the coadministration of tolcapone (by 65%, 74%, and 84% with tolcapone doses of 50, 200, and 400 mg, respectively, in fluctuators, and by 50% and 90% with doses of 200 and 400 mg, respectively, in nonfluctuators). This led to an overall reduction in levodopa clearance (CL) of approximately 15% to 25% in fluctuators and 20% to 30% in nonfluctuators. Because this was partly compensated for by a reduction in levodopa dose in these studies, the total daily exposure of patients to levodopa was only slightly increased (11% to 16%). The peak-trough fluctuations of plasma levodopa (Cmax–Cmin) were reduced in both populations in a dose-dependent fashion.
Conclusions: Tolcapone effectively inhibited the formation of 3-O-methyldopa and resulted in a decrease in levodopa CL. The consequent increase in levodopa bioavailability was mostly offset by reductions in levodopa dose. It is possible that decreased fluctuations in plasma levodopa concentrations rather than increased levodopa exposure may explain the clinical benefits obtained with tolcapone.
