Dingemanse J, Jorga K, Zürcher G, Fotteler B, Sedek G, Nielsen T, van Brummelen P
Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Eur J Clin Pharmacol. 1996;50(1-2):47-55. doi: 10.1007/s002280050068.
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.
The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio 1:1) 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.
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 Cmax and AUC values. Despite the long halflife 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 Emax 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.
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.
本研究旨在评估新型儿茶酚-O-甲基转移酶（COMT）抑制剂托卡朋在老年受试者中的多剂量临床药理学特性。
采用双盲、随机、安慰剂对照、剂量递增的多剂量设计，将四组每组八名老年受试者（男女比例1:1）按顺序给予托卡朋口服，每日三次，共7天，剂量分别为100、200、400和800毫克。在第2天和第7天，在首次服用托卡朋1小时后给予单剂量左旋多巴/苄丝肼100/25毫克。在研究过程中，测定托卡朋及其代谢产物3-O-甲基托卡朋、左旋多巴和3-O-甲基多巴的血浆浓度，并同时测定红细胞中的COMT活性。
托卡朋在所有剂量水平下耐受性良好，高剂量时女性胃肠道不良事件略有增加。该药物吸收和消除迅速，在每日三次100和200毫克的多剂量给药过程中，药代动力学未随时间变化。在每日三次400和800毫克的剂量下，托卡朋有中度蓄积，表现为Cmax和AUC值增加。尽管3-O-甲基托卡朋半衰期较长（39小时），但由于托卡朋对其形成的抑制作用，仅出现轻微蓄积。在治疗的一周内，托卡朋的药效学未发生变化，这体现在红细胞中COMT活性的抑制、血浆浓度-效应关系的推导参数（具有恒定EC50值的抑制性Emax模型）以及对左旋多巴药代动力学的影响（生物利用度增加1.6至2.5倍）。这表明不存在耐受性发展，且每日三次400和800毫克时药代动力学的改变对药效学无显著影响。
本研究结果为托卡朋作为左旋多巴辅助治疗帕金森病的应用提供了有前景的观点。
