OPTIMIZING LEVODOPA PHARMACOKINETICS WITH MULTIPLE TOLCAPONE DOSES INTHE ELDERLY

Objectives: The multiple-dose tolerability, pharmacokinetics, and phar macodynamics of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, were assessed in healthy elderly volunteers receiving conc omitant carbidopa and levodopa. Methods: Thirty-six volunteers from 55 to 75 years old participated in this double-blind, placebo-controlled , ascending multiple-dose study. Tolcapone was studied at dosages of 1 00, 200, 400, or 800 mg three times daily (t.i.d.) in four sequential groups. Each group consisted of nine participants who had been randomi zed to receive either placebo (n = 3) or tolcapone (n = 6). Tolcapone or placebo was coadministered with carbidopa and levodopa (25 and 100 mg, respectively) for 7 days. Assessments included tolerability, pharm acokinetics of tolcapone, levodopa, and 3-O-methyldopa, and inhibition of COMT activity in erythrocytes. Results: By inhibiting COMT, tolcap one reduced levodopa metabolism to 3-O-methyldopa, resulting in a twof old increase in levodopa exposure (area under the curve) and eliminati on half-life, without changing levodopa peak plasma concentration. The se effects were similar on days 1 and 7 of treatment, Development of t olerance to COMT inhibition was not observed. Onset of effect was rapi d (day 1 of treatment), and the maximum effect on levodopa pharmacokin etics was already observed with 100 or 200 mg tolcapone t.i.d. At thes e dosages, tolcapone pharmacokinetics were linear and stable; accumula tion occurred with 800 mg t.i.d. The combination of tolcapone and carb idopa-levodopa was generally well tolerated, although more nausea and vomiting were observed at higher dosages (400 to 800 mg t.i.d.), parti cularly in women. Conclusion: Tolcapone shows promise as an effective adjunct to levodopa in the treatment of Parkinson's disease. Clinical pharmacology data indicate that the therapeutic regimen should be 100 or 200 mg t.i.d.