Safety, Pharmacokinetics, and Pharmacodynamics Study in Healthy Subjects of Oral NEO6860, a Modality Selective Transient Receptor Potential Vanilloid Subtype 1 Antagonist - 06/10/17
Abstract |
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.
Perspective |
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.
Le texte complet de cet article est disponible en PDF.Highlights |
• | TRPV1 receptor is a key target for pain control, but previous developments of antagonists were terminated for safety concerns. |
• | NEO6860 is a modality selective TRPV1 antagonist, blocking capsaicin activation but not pH or heat activation. |
• | This study is a first in human phase I study establishing the preliminary safety and pharmacokinetics profile of NEO6860. Safety concerns observed with previous TRPV1 antagonists have not been observed in this study. |
• | Pharmacodynamics profile of NEO6860, using capsaicin intradermal, is consistent with an antagonist effect. |
Key words : NEO6860, TRPV1, first-in human, pharmacokinetics, pharmacodynamics, capsaicin test
Plan
| This study was sponsored by NEOMED Institute. |
|
| The authors are employees of NEOMED Institute (W.B., A.G., R.A., P.W., D.A.C.) or paid consultants of NEOMED Institute (R.L.L., S.H.). |
Vol 18 - N° 6
P. 726-738 - juin 2017 Retour au numéro
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