| Autor: |
Kraus, Richard L., Zhao, Fuqiang, Pall, Parul S., Zhou, Dan, Vardigan, Joshua D., Danziger, Andrew, Li, Yuxing, Daley, Christopher, Ballard, Jeanine E., Clements, Michelle K., Klein, Rebecca M., Holahan, Marie A., Greshock, Thomas J., Kim, Ronald M., Layton, Mark E., Burgey, Christopher S., Serra, Jordi, Henze, Darrell A., Houghton, Andrea K. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 5/19/2021, Vol. 13 Issue 594, p1-13, 13p |
| Abstrakt: |
Improving target engagement: Successful target engagement in vivo is a critical step in drug development. Targeting the voltage-gated sodium channel 1.7 (Nav1.7) with specific inhibitors holds promises for the treatment of chronic pain. However, inhibitors with good in vitro properties failed in the clinic. Now, Kraus et al. developed a protocol to guide dose calculation and determine target engagement of Nav1.7 inhibitors in nonhuman primates that could be translated to the clinic. The authors used microneurography of C-fibers, heat responsivity, and fMRI of the olfactory bulb to determine the plasma concentration required to produce channel inhibition of two potent Nav1.7 inhibitors. Adapted to humans, the results will help the development and interpretation of clinical trials testing Nav1.7 inhibitors. Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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