Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist.

Abstract

AIMS:

To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Carlijn Holland, Cornelis van Drunen, Jane Denyer, Kevin Smart, Christine Segboer, Ingrid Terreehorst, Amy Newlands, Misba Beerahee, Wytske Fokkens, Daphne C Tsitoura
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 77 Issue 5 Pg. 777-88 (May 2014) ISSN: 1365-2125 [Electronic] England
• PMID: 23909699 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Pyrrolidines
• SB 705498
• TRPV Cation Channels
• TRPV1 receptor
• Urea
• Capsaicin

Topics

• Adolescent
• Adult
• Capsaicin (antagonists & inhibitors)
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• Pyrrolidines (adverse effects, pharmacokinetics, pharmacology)
• Rhinitis (drug therapy)
• TRPV Cation Channels (antagonists & inhibitors)
• Urea (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology)
• Visual Analog Scale