Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects

Abstract.

Objective: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects.

Methods:

The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes.

Results:

Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased C_max and AUC values. Despite the long half-life of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone.

The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory E_max model with constant EC₅₀ values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics.

Conclusion:

The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson’s disease.