Tuunainen Johanna, Sjöstedt Noora, Vahteristo Mikko, Ellmén Juha, Kuoppamäki Mikko, Rouru Juha, Yliperttula Marjo
Orion Corporation Orion Pharma, Espoo, Finland.
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Eur J Drug Metab Pharmacokinet. 2023 Jan;48(1):23-34. doi: 10.1007/s13318-022-00800-w. Epub 2022 Oct 30.
The treatment of Parkinson's disease (PD) is still symptomatic since disease-modifying treatments for PD are not available. Oral levodopa is the gold standard for the treatment of PD motor symptoms. However, incomplete and fluctuating plasma exposure of levodopa leads to suboptimal treatment of the symptoms. The main objective of this study was to investigate to what extent increased carbidopa doses (50 and 100 mg) increase the plasma levels of 100-mg immediate-release (IR) levodopa compared to a 25-mg carbidopa dose with and without co-administration of 200 mg entacapone.
A double-blind, placebo-controlled, randomized, crossover, phase I, pharmacokinetic study with 25 healthy volunteers was conducted. In addition, a semi-mechanistic pharmacokinetic model was built to theoretically evaluate the effect of inhibiting aromatic amino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) mediated metabolism of levodopa on the exposure of levodopa.
The effect of increased carbidopa doses 50 and 100 mg on the total exposure (AUC) of 100 mg IR levodopa was +29% and +36%, respectively, when entacapone was co-administered. Without entacapone, the corresponding increases were +13% and +17%. With entacapone co-administration, the increased carbidopa dose also clearly increased levodopa trough concentration. There was no significant effect on the peak concentrations of levodopa.
Increasing carbidopa doses significantly increased the exposure and reduced the fluctuation of IR levodopa in plasma during simultaneous COMT inhibition with entacapone. Theoretical pharmacokinetic simulations suggested that the plasma profile of oral IR levodopa can be even further improved by optimizing AADC and COMT inhibition.
由于尚无帕金森病（PD）的疾病修饰治疗方法，PD的治疗仍以对症治疗为主。口服左旋多巴是治疗PD运动症状的金标准。然而，左旋多巴血浆暴露不完全且波动，导致症状治疗效果欠佳。本研究的主要目的是探究与25mg卡比多巴剂量相比，增加卡比多巴剂量（50mg和100mg）在联合或不联合使用200mg恩他卡朋的情况下，能在多大程度上提高100mg速释（IR）左旋多巴的血浆水平。
对25名健康志愿者进行了一项双盲、安慰剂对照、随机、交叉的I期药代动力学研究。此外，建立了一个半机制药代动力学模型，以从理论上评估抑制芳香族氨基酸脱羧酶（AADC）和儿茶酚-O-甲基转移酶（COMT）介导的左旋多巴代谢对左旋多巴暴露的影响。
联合使用恩他卡朋时，50mg和100mg卡比多巴剂量增加对100mg IR左旋多巴总暴露量（AUC）的影响分别为增加29%和36%。不使用恩他卡朋时，相应的增加分别为13%和17%。联合使用恩他卡朋时，增加卡比多巴剂量也明显提高了左旋多巴谷浓度。对左旋多巴的峰浓度无显著影响。
在与恩他卡朋同时抑制COMT的情况下，增加卡比多巴剂量可显著增加IR左旋多巴在血浆中的暴露量并减少其波动。理论药代动力学模拟表明，通过优化AADC和COMT抑制，口服IR左旋多巴的血浆曲线可得到进一步改善。
