Selonsertib 是一种细胞凋亡信号调节激酶 1 (ASK1) 抑制剂，在健康受试者中首次给药后的药代动力学、安全性和耐受性。,Clinical Pharmacokinetics

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Selonsertib 是一种细胞凋亡信号调节激酶 1 (ASK1) 抑制剂，在健康受试者中首次给药后的药代动力学、安全性和耐受性。
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2020-04-25 , DOI: 10.1007/s40262-020-00878-y
Cara H Nelson ₁ , Kim Etchevers ₁ , Saili Yi ₁ , David Breckenridge ₁ , Mischa Hepner ₁ , Uptal Patel ₁ , John Ling ₁ , Anita Mathias ₁

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背景 Selonsertib 是一种一流的细胞凋亡信号调节激酶 1 (ASK1) 抑制剂，具有治疗纤维化疾病的潜力。该 I 期研究评估了 selonsertib 在健康受试者中的安全性、耐受性、药代动力学 (PK) 和食物效应。方法这是一项双盲、随机、安慰剂对照的剂量递增研究。健康受试者在禁食状态下接受 1、3、10、30 或 100 mg selonsertib 或安慰剂作为单剂量或多剂量每天一次，持续 14 天，或在进食状态下接受 30 mg 或安慰剂单剂量。收集了 selonsertib PK 的血液和尿液（仅限单剂量组）样本，并在整个研究过程中评估了安全性。使用金诺芬刺激的 CXC 基序趋化因子配体 1 (CXCL1) 测定法在来自健康供体的单独队列的血液中进行体外药效学 (PD) 评估。结果总共有 107 名受试者（83 名积极分子，24 名安慰剂）被纳入并随机分配到 11 个队列。Selonsertib 总体耐受性良好；不良事件一般为轻度至中度。Selonsertib 被快速吸收，母体和非活性代谢物 GS-607509 的剂量成比例 PK。对 selonsertib PK 没有食物影响。肾脏排泄是 selonsertib 消除的次要途径。Selonsertib 在人全血中的半数最大有效浓度 (EC50) 被确定为 56 ng/mL。结论 Selonsertib 表现出有利的 PK 曲线，适合每天给药一次，而不考虑食物。PD 数据表明在评估的剂量范围内实现了药理学相关的暴露。研究结果支持 selonsertib 的进一步临床开发。

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Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects.

BACKGROUND Selonsertib is a first-in-class inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with therapeutic potential for fibrotic diseases. This phase I study evaluated the safety, tolerability, pharmacokinetics (PK), and food effect of selonsertib in healthy subjects. METHODS This was a double-blinded, randomized, placebo-controlled dose-escalation study. Healthy subjects received 1, 3, 10, 30, or 100 mg of selonsertib or placebo as single or multiple doses once daily for 14 days in the fasted state, or 30 mg or placebo single dose in the fed state. Blood and urine (single-dose cohorts only) samples for selonsertib PK were collected and safety was assessed throughout the study. Ex vivo pharmacodynamic (PD) assessment was performed in blood from a separate cohort of healthy donors using an auranofin-stimulated C-X-C motif chemokine ligand 1 (CXCL1) assay. RESULTS Overall, 107 subjects (83 active, 24 placebo) were enrolled and randomized to 11 cohorts. Selonsertib was generally well tolerated; adverse events were generally mild to moderate. Selonsertib was rapidly absorbed with dose-proportional PK of both parent and inactive metabolite GS-607509. There was no food effect on selonsertib PK. Renal excretion was a minor pathway of selonsertib elimination. Selonsertib half maximal effective concentration (EC50) in human whole blood was determined to be 56 ng/mL. CONCLUSIONS Selonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food. PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated. Study results support further clinical development of selonsertib.

更新日期：2020-04-25

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