Single‑Dose Pharmacokinetics and Safety of the Oral Galectin‑3 Inhibitor, Selvigaltin (GB1211), in Participants with Hepatic Impairment.

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical Drug Investigation Pub Date : 2024-10-01 Epub Date: 2024-10-02 DOI:10.1007/s40261-024-01395-7

Vassilios Aslanis, Michael Gray, Robert J Slack, Fredrik R Zetterberg, Dimitar Tonev, De Phung, Becky Smith, Brian Jacoby, Hans Schambye, Zahari Krastev, Anna-Lena Ungell, Bertil Lindmark

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Abstract

Background and objectives: Selvigaltin (GB1211), an orally available small molecule galectin-3 inhibitor developed as a treatment for liver fibrosis and cirrhosis, was evaluated to assess the effect of hepatic impairment on its pharmacokinetics and safety to address regulatory requirements.

Methods: GULLIVER-2 was a Phase Ib/IIa three-part study. Parts 1 and 3 had single-dose, open-label designs assessing pharmacokinetics (plasma [total and unbound] and urine), safety, and tolerability of 100 mg oral selvigaltin in participants with moderate (Child-Pugh B, Part 1) or severe (Child-Pugh C, Part 3) hepatic impairment, compared with healthy-matched participants (n = 6 each).

Results: All participants received selvigaltin and completed the study. No adverse events were reported. The median time to reach maximum total plasma concentration following drug administration was of 3.49 and 4.00 h post-dose for Child-Pugh B and C participants, respectively; comparable with controls. Total plasma exposure was higher for participants with hepatic impairment compared with controls. Whilst maximum plasma concentration (C_max) was unaffected in Child-Pugh B participants, area under the plasma concentration-time curve from time zero to infinity (AUC_∞) increased by ~ 1.7-fold compared with controls, and half-life was prolonged (geometric mean 28.15 vs 16.38 h). In Child-Pugh C participants, C_max increased by ~ 1.3-fold, AUC_∞ increased by ~ 1.5-fold, and half-life was prolonged (21.05 vs 16.14 h). No trend was observed in plasma unbound fractions or urinary excretion of unchanged selvigaltin in either group.

Conclusion: Hepatic impairment increased selvigaltin exposure without safety concerns. These data can inform dose recommendations for future clinical programmes.

Trial registration: Clinicaltrials.gov NCT05009680.

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肝功能不全患者口服 Galectin-3 抑制剂 Selvigaltin (GB1211) 的单剂量药代动力学和安全性。

背景和目的：Selvigaltin（GB1211）是一种口服小分子galcectin-3抑制剂，被开发用于治疗肝纤维化和肝硬化，为了满足监管要求，我们评估了肝功能损害对其药代动力学和安全性的影响：GULLIVER-2 是一项 Ib/IIa 期研究，共分三部分。方法：GULLIVER-2 是一项 Ib/IIa 期研究，共分三部分。第一部分和第三部分采用单剂量、开放标签设计，评估中度（Child-Pugh B，第一部分）或重度（Child-Pugh C，第三部分）肝功能受损者口服 100 毫克舍维加尔汀的药代动力学（血浆[总量和非结合量]和尿液）、安全性和耐受性，并与健康匹配者（n = 6 人）进行比较：所有参与者都接受了舍维加尔汀治疗并完成了研究。无不良事件报告。Child-Pugh B 级和 C 级参与者服药后达到最大血浆总浓度的中位时间分别为 3.49 小时和 4.00 小时；与对照组相当。与对照组相比，肝功能受损者的血浆总暴露量更高。虽然 Child-Pugh B 组患者的最大血浆浓度（Cmax）未受影响，但与对照组相比，从零时到无穷大的血浆浓度-时间曲线下面积（AUC∞）增加了约 1.7 倍，半衰期延长（几何平均数为 28.15 小时 vs 16.38 小时）。在 Child-Pugh C 参与者中，Cmax 增加了约 1.3 倍，AUC∞ 增加了约 1.5 倍，半衰期延长（21.05 小时 vs 16.14 小时）。两组患者的血浆未结合部分和尿液中未改变的舍曲格汀排泄量均无变化趋势：结论：肝功能损害会增加舍维加尔汀的暴露量，但不存在安全性问题。这些数据可为今后的临床计划提供剂量建议：试验注册：Clinicaltrials.gov NCT05009680。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Drug Investigation 医学-药学

CiteScore

5.90

自引率

3.10%

发文量

108

审稿时长

6-12 weeks

期刊介绍： Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes: -Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs. -Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice. -Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed. -Studies focusing on the application of drug delivery technology in healthcare. -Short communications and case study reports that meet the above criteria will also be considered. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Clinical Drug Investigation may be accompanied by plain language summaries to assist readers who have some knowledge, but non in-depth expertise in, the area to understand important medical advances.