The effect of intradermal microdosing of a transient receptor potential cation channel subfamily V member 1 antagonist on heat evoked pain and thermal thresholds in normal and ultraviolet‐C exposed skin in healthy volunteers

BACKGROUND: Three TRPV1 (Transient Receptor Potential Vanilloid Receptor 1) antagonists were developed for testing in situ in human skin (Sjogren et al., 2016; Sjogren et al., 2018; Sjogren et al., 2018). The first human study using these compounds and capsaicin, was performed to determine the required local antagonist concentrations needed for target engagement (Proof of Mechanism, PoM) (Sjogren et al., 2018). In this paper, the aim was to address a TRPV1 antagonist's ability to inhibit a more complex pain signal and to define translational endpoints that could be used in further drug development, when progressing orally bioavailable TRPV1 antagonists as novel analgesic medications. METHOD: This was a single centre, placebo-controlled, clinical proof of principle (PoP) study in 25 healthy volunteers. The subjects were exposed to UV irradiation, causing a local tissue inflammation. Three different doses of AZ12048189 were administered to assess pain perception through quantitative sensory testing (QST) and erythema using Laser Doppler scanning. RESULTS: AZ12048189 increased the warmth detection threshold (WDT) and the heat pain threshold (HPT) and decreased the intensity of supra threshold heat pain (STHP). AZ12048189 did not, however, have any significant effects as assessed using mechanical stimulation or Laser Doppler. CONCLUSIONS: This study validated translational tools to confirm target engagement for TRPV1 antagonists; WDT, HPT and STHP have utility in this respect, after oral administration of a TRPV1 antagonist. This study also proved that TRPV1 antagonists can inhibit a more complex, non-capsaicin dependent thermally induced pain signal.