在健康受试者中单次口服给予氘代 L-DOPA（SD-1077）/卡比多巴与 L-DOPA/卡比多巴的药代动力学、代谢和安全性比较。

Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects.

机构信息

Global Research and Development, Teva Pharmaceutical Industries, Berlin, Germany.

Global Research and Development, Teva Pharmaceutical Industries, West Chester, PA, USA.

出版信息

Br J Clin Pharmacol. 2018 Oct;84(10):2422-2432. doi: 10.1111/bcp.13702. Epub 2018 Aug 9.

AIMS

SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077.

METHODS

Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16).

RESULTS

Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for C , AUC , and AUC were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P < 0.0001) for C and AUC and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P = 0.0077) and 1.66 (1.42-1.93; P < 0.0001) for C and AUC , respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for C and AUC . SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD.

CONCLUSIONS

SD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.

目的

SD-1077 是一种选择性氘代多巴胺（DA）前体，与左旋 3,4-二羟基苯丙氨酸（L-DOPA）结构相关，目前正在开发用于治疗帕金森病的运动症状。临床前模型显示中央氘代 DA 的代谢速度较慢。本研究旨在研究 SD-1077 的外周药代动力学（PK）、代谢和安全性。

方法

在健康志愿者中进行了一项双盲、两周期交叉研究，比较了单次口服 150mg SD-1077 与 150mg L-DOPA 加 37.5mg 卡比多巴（CD）的药物和代谢物的血浆和尿液 PK 以及安全性（n=16）。

结果

SD-1077 与 L-DOPA 的 C 、 AUC 和 AUC 的几何最小二乘均值比（GMR）和 90%置信区间（90%CI）分别为 88.4（75.9-103.1）、89.5（84.1-95.3）和 89.6（84.2-95.4）。与 L-DOPA/CD 相比，SD-1077/CD 后 DA 的全身暴露显著增加，C 和 AUC 的 GMR（90%CI）分别为 1.8（1.45-2.24；P=0.0005）和 2.06（1.68-2.52；P<0.0001），同时 3,4-二羟基苯乙酸/DA 的比值降低，证实 MAO 对 DA 的代谢分解速度较慢。COMT 反应的代谢物 3-甲氧基酪胺（3-MT）和 3-O-甲基多巴（3-OMD）的全身暴露增加，SD-1077/CD 与 L-DOPA/CD 的 GMR（90%CI）分别为 3-MT 的 C 和 AUC 为 1.33（1.14-1.56；P=0.0077）和 1.66（1.42-1.93；P<0.0001），3-OMD 的 C 和 AUC 为 1.19（1.15,1.23；P<0.0001）和 1.31（1.27,1.36；P<0.0001）。SD-1077/CD 表现出与 L-DOPA/CD 相当的耐受性和安全性。