Brown William, Leff Richard L, Griffin Andrew, Hossack Stuart, Aubray Roxane, Walker Philippe, Chiche Dan A
NEOMED Institute, Montreal, Quebec, Canada.
Richard L. Leff, MD, LLC, Chadds Ford, Pennsylvania.
J Pain. 2017 Jun;18(6):726-738. doi: 10.1016/j.jpain.2017.01.009. Epub 2017 Feb 8.
Most previous transient receptor potential vanilloid subtype 1 (TRPV1) antagonist programs have been put on hold, mainly because of on-target adverse events: hyperthermia and impaired noxious heat sensation. NEO6860 is a TRPV1 antagonist, blocking capsaicin activation of the target, with little or no effect against pH or heat activation. The hypothesis is that this pharmacological profile will translate into analgesia without undesired effects on the body temperature or heat-pain threshold. This phase I, double blind, placebo controlled, ascending dose study, included 64 subjects. Pharmacodynamics (intradermal capsaicin test) was explored. The study was comprised of 6 dose levels (50, 100, 200, 400, 800, and 1,200 mg) and 2 doses of 500 mg, 12 hours apart. NEO6860 was rapidly absorbed and systemic exposure increases were less than dose proportional. Median time of maximum observed plasma concentration values ranged from 2 to 3 hours. The mean apparent plasma terminal elimination half-life was between 4 and 8 hours. No significant food-effect or gender-effect was observed. The most frequently reported events were feeling hot, headache, paresthesia, nausea, and dizziness. Single oral doses of up to 800 mg and two 500-mg doses administered 12 hours apart of NEO6860 were well tolerated in this study. Unlike other TRPV1 antagonists, no clinically significant increase in temperature or heat pain threshold/tolerance was noted despite thorough and specific monitoring of these parameters. At all doses, most subjects reported a sensation of "feeling hot," with a rapid onset and transient. NEO6860 showed an improvement in the pharmacodynamics parameters (evoked pain and secondary hyperalgesia) at 3 and 8 hours post NEO6860 dosing.
This first in human study on NEO6860, showed that an antagonist of TRPV1, blocking only the activation by capsaicin has been identified. This finding paves the way for the development of a new powerful analgesic for many pain conditions, without the fear of the side effects observed with previous TRPV1 antagonists.
此前大多数瞬时受体电位香草酸亚型1（TRPV1）拮抗剂项目已被搁置，主要是因为出现了靶点相关不良事件：体温过高和有害热感觉受损。NEO6860是一种TRPV1拮抗剂，可阻断辣椒素对靶点的激活，对pH值或热激活几乎没有影响。假设是这种药理学特性将转化为镇痛作用，而不会对体温或热痛阈值产生不良影响。这项I期双盲、安慰剂对照、剂量递增研究纳入了64名受试者。研究了药效学（皮内辣椒素试验）。该研究包括6个剂量水平（50、100、200、400、800和1200毫克）以及两剂500毫克，间隔12小时。NEO6860吸收迅速，全身暴露量的增加与剂量不成正比。最大观察血浆浓度值的中位时间为2至3小时。平均表观血浆终末消除半衰期在4至8小时之间。未观察到显著的食物效应或性别效应。最常报告的事件是感觉发热、头痛、感觉异常、恶心和头晕。在本研究中，单次口服高达800毫克以及间隔12小时服用两剂500毫克的NEO6860耐受性良好。与其他TRPV1拮抗剂不同，尽管对这些参数进行了全面且具体的监测，但未发现体温或热痛阈值/耐受性有临床显著升高。在所有剂量下，大多数受试者报告有“感觉发热”的感觉，起效迅速且短暂。NEO6860在给药后3小时和8小时时药效学参数（诱发疼痛和继发性痛觉过敏）有所改善。
这项关于NEO6860的首次人体研究表明，已鉴定出一种仅阻断辣椒素激活的TRPV1拮抗剂。这一发现为开发一种针对多种疼痛状况的新型强效镇痛药铺平了道路，而无需担心先前TRPV1拮抗剂所观察到的副作用。
