Research Headquarters, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Osaka, Japan.
Department of Research & Development, BIAL-Portela & C(a), S.A, 4745-457, São Mamede do Coronado, Portugal.
Neuropharmacology. 2018 Dec;143:282-288. doi: 10.1016/j.neuropharm.2018.10.001. Epub 2018 Oct 2.
The aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose.
Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24 h after the first and at 24 h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100 mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100 mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics.
Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100 mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100 mg/kg respectively, and COMT remained significantly inhibited at 24 h after 10 and 100 mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24 h was 15-25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration.
Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.
本研究旨在阐明第三代儿茶酚-O-甲基转移酶（COMT）抑制剂opicapone 在恒河猴体内的药代动力学特征，并评估急性和重复给药后 COMT 抑制作用的剂量反应。方法：本研究使用了 3 只恒河猴。在第一项实验中，采用交叉设计，在单次和 14 天连续口服给药后 24 小时，分别给予 1、10 和 100mg/kg 剂量的 opicapone，评估其对 COMT 抑制作用的 24 小时持续时间。在第二项实验中，在相同条件下重复测试最大有效剂量（100mg/kg），并额外监测血浆 opicapone 水平，以探索药代动力学与药效学之间的关系。结果：opicapone 呈剂量依赖性抑制 COMT 活性，在 10 和 100mg/kg 时显著抑制。1、10 和 100mg/kg 时最大抑制率分别为 13.1%、76.4%和 93.2%，在 10 和 100mg/kg 时，24 小时后 COMT 仍显著抑制（分别为 42.6%和 60.2%）。重复给予 opicapone 后，所有剂量在 24 小时时的残留 COMT 抑制率均增加了 15-25%。与药效学作用相反，opicapone 吸收迅速，消除迅速，连续给药 14 天后，血浆中无蓄积。结论：尽管 opicapone 从血浆中迅速消除，但仍表现出持续的、剂量依赖性的 COMT 抑制作用，且连续给药 14 天后，血浆中无蓄积证据。opicapone 满足了需要持续 COMT 抑制的化合物的需求，这将提高帕金森病患者左旋多巴的生物利用度。
