Vaz-da-Silva Manuel, Loureiro Ana I, Nunes Teresa, Lopes Carlos, Rocha José, Machado Rita, Costa Raquel, Torrão Leonel, Falcão Amílcar, Wright Lyndon, Almeida Luis, Soares-da-Silva Patrício
Department of Research & Development, BIAL, S. Mamede do Coronado, Trofa, Portugal.
Drugs R D. 2008;9(6):435-46. doi: 10.2165/0126839-200809060-00006.
Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet((R)) CR 200/50) in healthy subjects (n = 16).
This was a randomized, double-blind, placebo-controlled, four-way crossover study in healthy subjects, with at least 5 days of washout between treatment periods.
There was a dose-dependent and significant increase in levodopa extent of exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) without a significant change in peak exposure (maximum plasma concentration; [C(max)]). Using placebo as a reference, levodopa geometric mean ratios (GMRs) and 90% CIs following nebicapone 50 mg, 100 mg and 200 mg were, respectively, 1.13 (0.98, 1.30), 1.04 (0.90, 1.19) and 1.10 (0.96, 1.27) for C(max) and 1.26 (1.16, 1.34), 1.37 (1.27, 1.75) and 1.47 (1.42, 1.65) for AUC(infinity). For 3-O-methyldopa (3-OMD), the GMRs and 90% CIs were, respectively, 0.61 (0.55, 0.67), 0.45 (0.41, 0.50) and 0.33 (0.30, 0.36) for C(max) and 0.69 (0.61, 0.78), 0.53 (0.41, 0.61) and 0.41 (0.37, 0.47) for AUC(infinity). Nebicapone dose dependently and significantly decreased COMT activity. Maximum COMT inhibition occurred at 1.5-2.4 hours post-dose and ranged from 56% to 73% with nebicapone 50 mg and 200 mg, respectively. There was a good correlation between plasma concentrations of nebicapone and inhibition of S-COMT activity. Treatments were well tolerated.
Following concomitant administration with levodopa/carbidopa CR 200 mg/50 mg, single doses of nebicapone 50 mg, 100 mg and 200 mg significantly and dose-dependently inhibited S-COMT activity, increased systemic exposure to levodopa, and reduced 3-OMD formation.
左旋多巴是帕金森病（PD）最有效的对症治疗药物，但其使用常与运动并发症的发生相关。通过同时给予儿茶酚-O-甲基转移酶（COMT）抑制剂，可减少对多巴胺能刺激波动的这些不良反应。奈必卡朋是一种新型COMT抑制剂，目前正开发用于作为左旋多巴/多巴脱羧酶抑制剂的辅助药物治疗PD。本文旨在研究在健康受试者（n = 16）中，单次口服剂量（50 mg、100 mg和200 mg）的奈必卡朋与单次剂量控释（CR）左旋多巴/卡比多巴200 mg/50 mg（息宁（R）CR 200/50）合用时对左旋多巴药代动力学及红细胞可溶性COMT（S-COMT）活性的影响。
这是一项在健康受试者中进行的随机、双盲、安慰剂对照、四交叉研究，治疗期间之间至少有5天的洗脱期。
左旋多巴暴露程度（从零时间到无穷大的血浆浓度-时间曲线下面积[AUC（无穷大）]）呈剂量依赖性显著增加，而峰值暴露（最大血浆浓度；[C（max）]）无显著变化。以安慰剂为对照，奈必卡朋50 mg、100 mg和200 mg后的左旋多巴几何平均比值（GMRs）及90%置信区间（CIs），C（max）分别为1.13（0.98，1.30）、1.04（0.90，1.19）和1.10（0.96，1.27），AUC（无穷大）分别为1.26（1.16，1.34）、1.37（1.27，1.75）和1.47（1.42，1.65）。对于3-O-甲基多巴（3-OMD），C（max）的GMRs及90% CIs分别为0.61（0.55，0.67）、0.45（0.41，0.50）和0.33（0.30，0.36），AUC（无穷大）分别为0.69（0.61，0.78）、0.53（0.41，0.61）和0.41（0.37，0.47）。奈必卡朋剂量依赖性且显著降低COMT活性。最大COMT抑制作用在给药后1.5 - 2.4小时出现，奈必卡朋50 mg和分别为200 mg时，抑制率范围为56%至73%。奈必卡朋血浆浓度与S-COMT活性抑制之间存在良好相关性。治疗耐受性良好。
与左旋多巴/卡比多巴CR 200 mg/50 mg合用时，单次剂量50 mg、100 mg和200 mg的奈必卡朋显著且剂量依赖性地抑制S-COMT活性，增加左旋多巴的全身暴露，并减少3-OMD的形成。
