Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone.
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 co-administration 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.
Jorga
K
K
Department of Research and Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland. karin.jorga@roche.com
Banken
L
L
Fotteler
B
B
Snell
P
P
Steimer
J L
JL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001577:Benzophenones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065098:Catechol O-Methyltransferase Inhibitors; D017322:Clinical Trials, Phase II as Topic; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007980:Levodopa / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D015337:Multicenter Studies as Topic; D009596:Nitrophenols; D010300:Parkinson Disease / Q000097:blood* / Q000188:drug therapy; D011159:Population Surveillance; D016032:Randomized Controlled Trials as Topic; D000077867:Tolcapone
D000978:Antiparkinson Agents; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D007980:Levodopa; D000077867:Tolcapone