TY - JOUR
T1 - Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist
AU - Holland, Carlijn
AU - van Drunen, Cornelis
AU - Denyer, Jane
AU - Smart, Kevin
AU - Segboer, Christine
AU - Terreehorst, Ingrid
AU - Newlands, Amy
AU - Beerahee, Misba
AU - Fokkens, Wytske
AU - Tsitoura, Daphne C.
PY - 2014
Y1 - 2014
N2 - To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist. Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge. Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and Cmax , while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2- to 4-fold shift in capsaicin potency. Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluation
AB - To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist. Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge. Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and Cmax , while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2- to 4-fold shift in capsaicin potency. Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluation
U2 - https://doi.org/10.1111/bcp.12219
DO - https://doi.org/10.1111/bcp.12219
M3 - Article
C2 - 23909699
SN - 0306-5251
VL - 77
SP - 777
EP - 788
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 5
ER -