Misselwitz Frank, Henderson Dennis, Menakuru Somasekhara R, Morten Elaine, Roe Chris, Whitaker Gareth, Wohlfeil Stefan, McDermott John
Actimed Therapeutics, London, UK.
Quotient Sciences, Nottingham, UK.
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13651. doi: 10.1002/jcsm.13651. Epub 2024 Dec 12.
S-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.
This 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.
Parts 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 (T 1 vs. 1.5 h; C 74 vs. 73.6 ng/mL; AUC 440 vs. 414 ng·h/mL; t 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 C, AUC and AUC 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.
Data 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.
S-吲哚洛尔在癌症恶病质中具有潜在有益的代谢作用：通过非选择性β受体阻滞减少分解代谢；通过部分β2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-吲哚洛尔可逆转癌症相关体重减轻患者的体重减轻并改善去脂体重。进行了一项S-吲哚洛尔和消旋吲哚洛尔的比较性I期生物利用度研究，以支持S-吲哚洛尔在癌症恶病质中的开发。
这项两部分的研究评估了单剂量苯甲酸S-吲哚洛尔（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）。测试了ACM-001.1 5、10和15mg以及吲哚洛尔15、20和30mg。在第1部分中，受试者被随机分配接受15mg的ACM-001.1，在48小时的洗脱期后接受30mg的吲哚洛尔，或相反顺序；另一组接受15mg的吲哚洛尔。第2部分的受试者被随机分配接受每日两次20mg的吲哚洛尔或每日两次5、10或15mg的ACM-001.1，持续4天。评估了生物利用度、药代动力学、药效学、立体转化的可能性和程度以及耐受性。
第1部分和第2部分分别纳入了24名和27名健康志愿者。ACM-001.1在每日两次高达15mg的剂量下具有可预测的药代动力学，单剂量和多剂量后受试者间变异性低（T 1对1.5小时；C 74对73.6ng/mL；AUC 440对414ng·h/mL；t 4.042对3.566小时）。等量的吲哚洛尔（20mg）和ACM-001.1（10mg）后S-吲哚洛尔的生物利用度相当，且达到了正式的生物等效性界限（C、AUC和AUC的90%置信区间在80%-125%生物等效性接受标准内）。没有证据表明S-对映体向R-对映体的立体转化，未显示S-吲哚洛尔在一系列剂量范围内的蓄积、剂量线性和剂量比例性；我们还间接表明没有食物效应。ACM-001.1总体耐受性良好，副作用与剂量无明显关系，无严重不良事件、严重治疗中出现的不良事件（TEAE）或死亡，ACM-001.1 10和15mg与吲哚洛尔20mg的TEAE（疲劳、头晕、嗜睡、恶心和头痛）发生率相似。
这项对映体纯的ACM-001.1及其母体消旋药物吲哚洛尔的桥接研究数据支持ACM-001.1治疗癌症恶病质的临床试验。
