PO.CL11.02 · 临床研究
Ketamir-2：一种用于化疗诱导的周围神经病变的新型口服氯胺酮类似物
Ketamir-2, a novel oral ketamine analogue for chemotherapy-induced peripheral neuropathy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：Ketamir-2是一种新一代氯胺酮类似物，旨在相对于现有的基于氯胺酮的疼痛疗法改善口服生物利用度和安全性。它作为一种低亲和力的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂发挥作用，选择性结合苯环己哌啶（PCP）位点，据信这一机制是其镇痛潜力的基础，同时减少了分离性效应。
方法与结果：在临床前研究中，口服给予Ketamir-2（双羟萘酸盐）在已确立的神经病理性疼痛啮齿动物模型中产生了显著的镇痛活性，包括大鼠的Chung脊神经结扎模型和小鼠的paclitaxel诱导的机械性痛觉超敏模型。在这两种模型中，Ketamir-2与口服氯胺酮以及作为阳性对照的标准神经病理性疼痛药物pregabalin和gabapentin相比，均显示出更优的疗效。药理学分析证实其具有强大的口服生物利用度且不具有P-糖蛋白（P-gp）底物活性，支持其高效穿透血脑屏障——这是中枢神经系统（CNS）治疗药物的一项必备特性。值得注意的是，Ketamir-2表现出良好的安全性，未见氯胺酮通常出现的分离性或致幻性副作用。
临床开发：将展示首次人体（FIH）研究的结果。这项随机、双盲、安慰剂对照的1期试验在Hadassah Medical Center临床药理学部开展，评估了Ketamir-2在健康成年志愿者中的安全性、耐受性和药代动力学。共有56名参与者被纳入单次递增剂量（SAD）和多次递增剂量（MAD）队列。
结论：这些发现支持Ketamir-2作为一种有前景的口服NMDA受体调节剂，用于治疗化疗诱导的周围神经病变（CIPN）和其他神经病理性疼痛疾病，提供了兼具疗效、安全性和口服便利性的差异化特征。
查看英文原文 English abstract
Background: Ketamir-2 is a next-generation ketamine analogue designed to improve oral bioavailability and safety relative to existing ketamine-based pain therapies. It acts as a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist with selective binding to the phencyclidine (PCP) site, a mechanism believed to underlie its analgesic potential while reducing dissociative effects.
Methods and Results: In preclinical studies, oral administration of Ketamir-2 (pamoate salt) produced significant analgesic activity across established rodent models of neuropathic pain, including the Chung spinal nerve ligation model in rats and the paclitaxel-induced mechanical allodynia model in mice. In both models, Ketamir-2 demonstrated superior efficacy compared with oral ketamine and the standard neuropathic pain agents pregabalin and gabapentin, which served as positive controls. Pharmacological profiling confirmed robust oral bioavailability and lack of P-glycoprotein (P-gp) substrate activity, supporting its efficient penetration across the blood-brain barrier-an essential property for central nervous system (CNS) therapeutics. Notably, Ketamir-2 exhibited a favorable safety profile with no evidence of dissociative or psychedelic side effects typically observed with ketamine.
Clinical Development: Results from the first-in-human (FIH) study will be presented. This randomized, double-blind, placebo-controlled Phase 1 trial, conducted at the Clinical Pharmacology Unit of Hadassah Medical Center, evaluated the safety, tolerability, and pharmacokinetics of Ketamir-2 in healthy adult volunteers. A total of 56 participants were enrolled across single-ascending-dose (SAD) and multiple-ascending-dose (MAD) cohorts.
Conclusions: These findings support Ketamir-2 as a promising oral NMDA-receptor modulator for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) and other neuropathic pain disorders, offering a differentiated profile combining efficacy, safety, and oral convenience.
利益披露 Disclosure
I. Angel, None..
C. Yoseph, None..
E. Aminov, None.