Utreloxastat (PTC857) 的药代动力学和安全性的首次人体研究，一种用于治疗肌萎缩性侧索硬化症的新型 15-脂加氧酶抑制剂,Clinical Pharmacology in Drug Development

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Utreloxastat (PTC857) 的药代动力学和安全性的首次人体研究，一种用于治疗肌萎缩性侧索硬化症的新型 15-脂加氧酶抑制剂
Clinical Pharmacology in Drug Development ( IF 1.5 ) Pub Date : 2022-12-14 , DOI: 10.1002/cpdd.1203
Lan Gao ₁ , Peter Giannousis ₁ , Martin Thoolen ₁ , Diksha Kaushik ₁ , Joey Latham ₁ , Aaron Tansy ₁ , Jiyuan Ma ₁ , Mayzie Johnston ₁ , Mandar Dali ₁ , Lee Golden ₁ , Matthew Klein ₁ , Ronald Kong ₁ , Jeffrey Trimmer ₁

Affiliation

Utreloxastat (PTC857) 是一种 15-脂氧合酶抑制剂，正在开发用于治疗肌萎缩侧索硬化症。这项首次人体研究在一项双盲、安慰剂对照试验中调查了健康志愿者 (N = 82) 中乌曲司他的安全性和药代动力学。评估了单次递增剂量（100-1000 mg）、多次递增剂量（150-500 mg）和食物（500 mg）对乌曲司他药代动力学和安全性的影响。_{单次给药后，观察到达到最大血浆浓度 (C max} )的时间约为给药后 4 小时，终末半衰期范围为 20 至 25.3 小时。C_最大值浓度-时间曲线下面积 (AUC) 随剂量增加而略有增加。多次给药后（每天一次/每天两次），表观清除率降低，终末半衰期≥33小时。早上或晚上剂量后的暴露没有明显差异。不同的饮食增加了 utreloxastat 的 C _max和 AUC，但没有改变达到 C _max的时间。在暴露方面没有基于性别的差异。Utreloxastat 在单次剂量高达 1000 mg 和超过 14 天的多次剂量（500 mg 每天一次或 250 mg 每天两次）后没有显示出明显的安全信号。该结果支持进一步开发 utreloxastat 用于治疗肌萎缩侧索硬化症患者，剂量为 250 mg，每日两次，随餐服用。

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First-in-Human Studies of Pharmacokinetics and Safety of Utreloxastat (PTC857), a Novel 15-Lipooxygenase Inhibitor for the Treatment of Amyotrophic Lateral Sclerosis

Utreloxastat (PTC857) is a 15-lipoxygenase inhibitor being developed to treat amyotrophic lateral sclerosis. This first-in-human study investigated the safety and pharmacokinetics of utreloxastat in healthy volunteers (N = 82) in a double-blind, placebo-controlled trial. The effects of a single ascending dose (100–1000 mg), multiple ascending doses (150–500 mg), and food (500 mg) on the pharmacokinetics and safety of utreloxastat were evaluated. Following single doses, the time to maximum plasma concentration (C_max) was observed ≈4 hours after dosing and the terminal half-life ranged from 20 to 25.3 hours. The C_max and area under the concentration-time curve (AUC) increased slightly over dose proportionally. Following multiple doses (once daily/twice daily), the apparent clearance reduced and terminal half-life was ≥33 hours. There was no apparent difference of exposure following morning or evening doses. Varying diets increased the C_max and AUCs of utreloxastat but did not alter time to C_max. There were no gender-based differences in exposure. Utreloxastat showed no marked safety signal following single doses up to 1000 mg and multiple doses over 14 days of 500 mg once daily or 250 mg twice daily. The results support further development of utreloxastat for the treatment of patients with amyotrophic lateral sclerosis at a 250-mg twice-daily dose administered with food.

更新日期：2022-12-14

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