Department of Neurology, Wayne State University School of Medicine and Henry Ford Hospital, Detroit, MI.
Neurocrine Biosciences, Inc, San Diego, CA.
Clin Neuropharmacol. 2023;46(2):43-50. doi: 10.1097/WNF.0000000000000538. Epub 2023 Jan 21.
Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease.
Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented.
Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased.
Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.
左旋多巴（LD）与多巴胺脱羧酶抑制剂联合使用时，主要在外周通过儿茶酚-O-甲基转移酶（COMT）代谢为 3-O-甲基多巴（3-OMD）。COMT 抑制可通过降低循环 LD 浓度的变异性来改善治疗效果。阿扑卡朋是一种每日一次的 COMT 抑制剂，在美国被批准与卡比多巴（CD）/LD 联合用于帕金森病患者，以治疗“OFF”发作。本研究旨在评估每日一次阿扑卡朋 50mg 与稳定帕金森病患者的 CD/LD 联合应用的药代动力学和药效动力学。
每日一次给予阿扑卡朋 50mg，连续 14 天，每晚一次。参与者被随机分配接受每 3 或 4 小时（Q3H 或 Q4H）一次的 CD/LD（25/100mg）。参与者在第 1、2 和 15 天接受 Q3H 或 Q4H CD/LD，其余时间接受其常规 CD/LD 方案。连续采集血样以确定血浆阿扑卡朋、LD 和 3-OMD 浓度和红细胞可溶性 COMT（S-COMT）活性。评估阿扑卡朋对 S-COMT、LD 和 3-OMD 的影响。呈现均值（标准差）值。
共纳入 16 名参与者。在稳态（第 14 天）时，阿扑卡朋 Cmax（血浆峰浓度）和 AUC0-last（曲线下时间曲线面积）分别为 459±252ng/mL 和 2022±783ng/mL·h。第 14 天时 COMT 最大抑制率为基线的 83.4±4.9%。给予阿扑卡朋后，LD 总 AUC、峰浓度和谷浓度增加；峰谷波动指数降低。相应地，3-OMD 总 AUC、峰浓度和谷浓度降低。
每日一次给予阿扑卡朋 50mg 可显著延长 COMT 抑制，增加 LD 的全身暴露。这些变化转化为 LD 的谷浓度升高和峰谷波动减少。
