A DOUBLE-BLIND PHARMACOKINETIC AND CLINICAL DOSE-RESPONSE STUDY OF ENTACAPONE AS AN ADJUVANT TO LEVODOPA THERAPY IN ADVANCED PARKINSONS-DISEASE

A dose-response study of the effects of entacapone on the pharmacokine tics and metabolism of levodopa and on the clinical response to levodo pa was carried out in 20 parkinsonian patients with levodopa-related f luctuations. A randomized, double-blind, single-graded-dose, crossover design of five 1-day treatment periods each 1 week apart was used. En tacapone (50, 100, 200, or 400 mg) or placebo was given at 8 a.m. with the patient's individual dose of levodopa/dopa decarboxylase inhibito r. The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) and plasma concentrations of levodopa, its meta bolites, and entacapone were measured and motor responses were quantif ied at 30-min intervals using the motor part of the Unified Parkinson' s Disease Rating Scale. Entacapone brought about a dose-dependent decr ease in S-COMT activity in the RBCs, maximally by 48% at 400 mg. With a 200-mg dose of entacapone, the area under the plasma concentration-t ime curve (AUG) and half-life of levodopa increased (p < 0.001); the A UCs of 3-O-methyldopa and homovanillic acid decreased (p = 0.01 and p < 0.001, respectively) and that of 3,4-dihydroxyphenylacetic acid incr eased (p < 0.001). Entacapone prolonged the duration of the motor resp onse to levodopa by 33 min (p = 0.04) and dyskinesias by 45 min (p = 0 .003) without affecting their magnitude; the highest increase in durat ion of these responses occurred with 200 mg of entacapone. Thus, on ph armacokinetic and clinical grounds, the 200-mg dose of entacapone was the most effective. Dose-related responses to entacapone demonstrated its value in the treatment of parkinsonian patients with levodopa-rela ted fluctuations by prolonging the antiparkinsonian response to the le vodopa dose.