BackgroundS‐pindolol has metabolic effects of potential benefit in cancer cachexia: reduced catabolism through nonselective β‐blockade; increased anabolism through partial β2 receptor agonism; and increased appetite and reduced fatigue through central 5‐hydroxytryptamine/serotonin receptor activity. A Phase 2a clinical trial demonstrated that S‐pindolol can reverse weight loss and improve fat‐free mass in patients with cancer‐related weight loss. A comparative phase I bioavailability study of S‐pindolol and racemic pindolol was performed to support the development of S‐pindolol in cancer cachexia.MethodsThis two‐part study assessed the comparative bioavailability and pharmacokinetics of single doses of S‐pindolol benzoate (ACM‐001.1) or pindolol (Part 1) and the steady‐state pharmacokinetics and pharmacodynamics of multiple doses of ACM‐001.1 and pindolol (Part 2) in healthy volunteers (NCT06028321). ACM‐001.1 5, 10 and 15 mg and pindolol 15, 20 and 30 mg were tested. In Part 1, subjects were randomised to ACM‐001.1 15 mg followed after a 48‐h washout period by pindolol 30 mg, or the reverse sequence; another group received pindolol 15 mg. Subjects in Part 2 were randomised to pindolol 20 mg twice‐daily or ACM‐001.1 5, 10 or 15 mg twice‐daily for 4 days. Bioavailability, pharmacokinetics, pharmacodynamics, potential for and extent of stereoconversion, and tolerability were assessed.ResultsParts 1 and 2 included 24 and 27 healthy volunteers, respectively. ACM‐001.1 had predictable pharmacokinetics up to a dose of 15 mg twice daily, with low intersubject variability, after single and multiple doses (Tmax 1 vs. 1.5 h; Cmax 74 vs. 73.6 ng/mL; AUC(0−t) 440 vs. 414 ng·h/mL; t1/2 4.042 vs. 3.566 h). The bioavailability of S‐pindolol after equivalent doses of pindolol (20 mg) and ACM‐001.1 (10 mg) was comparable, and formal bioequivalence margins were met (90% CI for Cmax, AUC(0−t) and AUC(0–inf) within 80%–125% bioequivalence acceptance criteria). No evidence of stereoconversion of the S‐enantiomer into the R‐enantiomer, no accumulation, dose linearity and dose proportionality of S‐pindolol over a range of doses were demonstrated; we also show indirectly that there was no food effect. ACM‐001.1 was generally well tolerated, with no apparent relationship of side effects to dose, no serious adverse events, severe treatment‐emergent adverse events (TEAEs) or deaths, and similar incidences of TEAEs (fatigue, dizziness, somnolence, nausea and headache) with ACM‐001.1 10 and 15 mg and pindolol 20 mg.ConclusionsData from this bridging study of enantiomerically pure ACM‐001.1 and its parent racemic drug, pindolol, support clinical trials of ACM‐001.1 for the treatment of cancer cachexia.

中文翻译：

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ACM-001.1（S-苯甲酸吲哚洛尔）在健康志愿者中的药代动力学、药效学和生物利用度


背景S-吲哚洛尔在癌症恶病质中具有潜在益处的代谢作用：通过非选择性 β 阻断减少分解代谢;通过部分 β 2 受体激动作用增加合成代谢;以及通过中枢 5-羟色胺/血清素受体活性增加食欲和减轻疲劳。一项 2a 期临床试验表明，S-吲哚洛尔可以逆转癌症相关体重减轻患者的体重减轻并改善无脂肪质量。进行了 S-吲哚洛尔和外消旋吲哚洛尔的 I 期生物利用度比较研究，以支持 S-吲哚洛尔在癌症恶病质中的发展。方法这项分为两部分的研究评估了单剂量 S-吲哚洛尔苯甲酸盐 （ACM-001.1） 或吲哚洛尔（第 1 部分）的比较生物利用度和药代动力学，以及多剂量 ACM-001.1 和吲哚洛尔（第 2 部分）在健康志愿者中的稳态药代动力学和药效学 （NCT06028321）。测试 ACM-001.1 5、10 和 15 mg 以及吲哚洛尔 15、20 和 30 mg。在第 1 部分中，受试者被随机分配到 ACM-001.1 15 mg，然后在 48 小时清除期后使用 30 mg 吲哚洛尔，或按相反顺序;另一组接受 15 mg 吲哚洛尔。第 2 部分中的受试者被随机分配到吲哚洛尔 20 毫克，每天两次或 ACM-001.1 5、10 或 15 毫克，每天两次，持续 4 天。评估了生物利用度、药代动力学、药效学、立体转换的潜力和程度以及耐受性。结果第 1 部分和第 2 部分分别包括 24 名和 27 名健康志愿者。ACM-001.1 在单次和多次给药后，剂量高达 15 mg，每天两次，具有较低的受试者间变异性（Tmax 1 vs. 1.5 h;Cmax 74 与 73.6 ng/mL;AUC（0−t） 440 vs. 414 ng·h/mL;t1/2 4.042 对 3.566 h）。 在等剂量的吲哚洛尔 （20 mg） 和 ACM-001.1 （10 mg） 后，S-吲哚洛尔的生物利用度相当，并且满足正式的生物等效性边缘（Cmax 的 90% CI，AUC（0-t） 和 AUC（0-inf） 在 80%-125% 生物等效性接受标准内）。没有证据表明 S-对映异构体立体转化为 R-对映异构体，在一定剂量范围内没有证明 S-吲哚洛尔的积累、剂量线性和剂量比例;我们还间接地表明没有食物效应。ACM-001.1 总体耐受性良好，副作用与剂量没有明显关系，无严重不良事件、严重治疗中出现的不良事件 （TEAE） 或死亡，以及 ACM-001.1 10 和 15 mg 和吲哚洛尔 20 mg 的 TEAE 发生率相似（疲劳、头晕、嗜睡、恶心和头痛）。结论这项对映体纯 ACM-001.1 及其母体外消旋药物吲哚洛尔的桥接研究的数据支持 ACM-001.1 治疗癌症恶病质的临床试验。