Abstract
Pharmacological challenge models are deployed to evaluate drug effects during clinical development. Intradermal injection of Substance P (SP) neuropeptide, a potential challenge agent for investigating local mediators, is associated with wheal and flare response mediated by the MRGPRX2 receptor. Although dose-dependent data on SP effects exist, full characterization and information on potential carryover effect after repeated challenge are lacking. This open-label, two-part, prospective enabling study of SP intradermal challenge in healthy participants aimed to understand and distinguish between wheal and flare responses following various SP doses. Part 1 included one challenge visit to determine optimum SP dose range for evaluation in part 2, which determined variability in 20 participants and used intradermal microdialysis (IDM) for SP-challenged skin sampling. At 5, 15, 50, and 150 pmol doses, respectively, posterior median area under the curve (AUC; AUC0–2h) was 4090.4, 5881.2, 8846.8, and 9212.8 mm2/min, for wheal response, and 12020.9, 38154.3, 65470.6, and 67404.4 mm2/min for flare response (SP-challenge visit 2). When the challenge was repeated ~2 weeks later, no carryover effect was observed. IDM histamine levels were relatively low, resulting in low confidence in the data to define temporal characteristics for histamine release following SP challenge. No safety concerns were identified using SP. Wheal and flare responses following intradermal SP challenge were dose-dependent and different. The results indicate that this challenge model is fit-for-purpose in future first-in-human studies and further assessment of novel drugs targeting dermal inflammatory disease responses, such as chronic spontaneous urticaria, chronic inducible urticaria, and pseudo-allergic reactions.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Clinical and Translational Science |
| Vol/bind | 16 |
| Udgave nummer | 10 |
| Sider (fra-til) | 1856-1865 |
| Antal sider | 10 |
| ISSN | 1752-8054 |
| DOI | |
| Status | Udgivet - okt. 2023 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:The authors thank the participants and the site staff for their contribution to the clinical study. All authors had access to the study data, take responsibility for the accuracy of the analysis, contributed to data interpretation, reviewed, and contributed to the content of the manuscript, and had authority in the decision to submit the manuscript. Medical writing support for the development of this manuscript, under direction of the authors, was provided by Suzan Maboane, MSc, of Ashfield MedComms, an Inizio company, and funded by GSK. Collaborators: Frank Sinner, Gerd Schwagerle, Joanneum Research Forschungsgesellschaft mhH, Institut HEALTH, Graz, Austria, and Per Stahl Skov, RefLab ApS, Copenhagen, Denmark.
Funding Information:
W.tV., I.A., S.W., N.K., M.B., M.vD., and R.R. are employees of the Centre for Human Drug Research which received funding from GSK to conduct this study. C.A., R.K., K.F., A.N., L.F., C.M., S.M., and R.B. are employees of and shareholders in GSK. K.B. is an employee of RefLab ApS which received funding from GSK to conduct this study. S.H. was an employee of and shareholder in GSK at the time of study.
Funding Information:
This study was supported by GSK (study number 213224).
Publisher Copyright:
© 2023 GlaxoSmithKline. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.