新型钆基MRI造影剂Gadoquatrane在雌性食蟹猴体内的药代动力学、排泄和器官分布。

IF 8 1区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Clemens Guenther, Thomas Frenzel, Antje Rottmann, Jessica Lohrke, Wiebke Janssen
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引用次数: 0

摘要

目的:Gadoquatrane是一种四聚体、大环、细胞外钆基MRI造影剂,具有高弛豫性和稳定性,目前处于3期临床开发。本研究的目的是表征gadoquatrane在与人类密切相关的动物物种中的药代动力学特征,并将其与两种长期建立的钆基造影剂gadobutrol和gadoterate (Gd-DOTA)的特征进行比较,或者更准确地说,与这些药物的类似物进行比较。用非钆基镧系类似物代替钆基镧系类似物,使共注入的3种化合物可解析微导。材料与方法:选取雌性食蟹猴8只。6只动物单次静脉注射含有相同剂量(0.1 mmol镧系元素/kg体重)的gadoquatrane、dyy -butrol和Tb-DOTA的混合物。两只对照动物接受安慰剂。程序包括在给药后58天收集血液、排泄物和选定的组织样本。采用电感耦合等离子体质谱法测定了所有样品中镧系化合物的浓度。镧系元素血浆浓度拟合为3室模型以获得药代动力学参数。采用高效液相色谱与电感耦合等离子体质谱或高分辨率体质谱相结合的方法对gadoquatrane的代谢物进行分析。结果:注射后加多四烷血药浓度呈3个阶段下降:分布期(α-期;半衰期:~3 min),主要消除相(β-相;半衰期:~60 min)和缓慢的终端消除相(γ-相;半衰期:约25小时)。有效半衰期为~1.0 h,总血浆清除率为0.11 L/kg/h,分布容积为0.17 L/kg。Gadoquatrane迅速且几乎完全通过肾脏排出。平均而言,97%的剂量(SD: 5.3%)在注射后24小时内从尿液中回收。尿排泄在第58天仍在继续,尽管量很小(0.01%剂量/天)。在器官和组织样本中仅检测到微量的Gd(结论:Gadoquatrane的药代动力学特征与大环比较物产品非常相似。在本研究中,与对照产品相比,服用gadoquatrane后,没有迹象表明组织中钆长期存在的风险增加。代谢物分析证实了gadoquatrane的代谢稳定性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetics, Excretion, and Organ Distribution of the Novel Gadolinium-Based MRI Contrast Agent Gadoquatrane in Female Cynomolgus Monkeys.

Objectives: Gadoquatrane is a tetrameric, macrocyclic, extracellular gadolinium-based MRI contrast agent with high relaxivity and stability, which is currently in Phase 3 clinical development. The aim of the present study was to characterize the pharmacokinetic profile of gadoquatrane in an animal species closely related to humans and to compare this profile with the profiles of the 2 long-established gadolinium-based contrast agents gadobutrol and gadoterate (Gd-DOTA) or, more precisely, with analogs of these agents. Non-Gd-based lanthanide analogs were used instead of the Gd-based versions to make the 3 co-injected compounds analytically differentiable.

Materials and methods: Eight female cynomolgus monkeys were included. Six animals received a single intravenous injection of a mixture containing gadoquatrane, Dy-butrol and Tb-DOTA at the same dose (0.1 mmol lanthanide/kg body weight). Two control animals received placebo. Procedures included collection of blood, excreta, and selected tissue samples up to 58 days post dose. Inductively coupled plasma mass spectrometry was used to measure the concentrations of the lanthanide complexes in all samples. Lanthanide plasma concentrations were fitted to a 3-compartment model to obtain pharmacokinetic parameters. High-performance liquid chromatography connected to inductively coupled plasma mass spectrometry or high-resolution mass spectroscopy was used for metabolite profiling of gadoquatrane.

Results: After the injection, gadoquatrane plasma concentrations decreased in 3 phases: a distribution phase (α-phase; half-life: ~3 min), a major elimination phase (β-phase; half-life: ~60 min), and a slow terminal elimination phase (γ-phase; half-life: approximately 25 h). The effective half-life was ~1.0 hour, the total plasma clearance was 0.11 L/kg/h, and the volume of distribution was 0.17 L/kg. Gadoquatrane was rapidly and almost exclusively renally excreted. On average, 97% of the dose (SD: 5.3%) was recovered in urine within the first 24 hours after the injection. Urinary excretion was still ongoing at day 58, albeit in very small quantities (0.01% of dose/day). Only minimal amounts of Gd were detected in organ and tissue samples (<110 ppm dose/g tissue at day 5 and <10 ppm dose/g tissue at day 58). The highest concentration was found in the kidney cortex at day 5 (41 nmol Gd/g tissue). The Gd concentrations in skin and selected brain sections were lower by a factor of 100 or 1000, respectively, at day 5. Gd tissue concentrations declined substantially in all tested tissues between day 5 and day 58. Similar results were obtained for Dy-butrol and Tb-DOTA. Metabolic degradation of gadoquatrane was not observed.

Conclusions: Gadoquatrane showed a pharmacokinetic profile very similar to that of macrocyclic comparator products. There were no indications of an increased risk of a prolonged presence of gadolinium in tissues in this study after administration of gadoquatrane compared with the comparator products. Metabolite profiling confirmed the metabolic stability of gadoquatrane.

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来源期刊
Investigative Radiology
Investigative Radiology 医学-核医学
CiteScore
15.10
自引率
16.40%
发文量
188
审稿时长
4-8 weeks
期刊介绍: Investigative Radiology publishes original, peer-reviewed reports on clinical and laboratory investigations in diagnostic imaging, the diagnostic use of radioactive isotopes, computed tomography, positron emission tomography, magnetic resonance imaging, ultrasound, digital subtraction angiography, and related modalities. Emphasis is on early and timely publication. Primarily research-oriented, the journal also includes a wide variety of features of interest to clinical radiologists.
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