First‐in‐human development of a pharmacodynamic biomarker for PAC1 receptor antagonists using intradermal injections of maxadilan

Autor: Heleen Marynissen, Linde Buntinx, Dorien Bamps, Marleen Depre, Els Ampe, Anne Van Hecken, Kristin Gabriel, Steve Sands, Gabriel Vargas, Jan de Hoon
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Clinical and Translational Science, Vol 15, Iss 8, Pp 1968-1977 (2022)
Druh dokumentu: article
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.13309
Popis: Abstract Maxadilan, a potent vasodilator peptide, selectively activates the PAC1 receptor, a promising target for migraine therapy. Therefore, maxadilan has been suggested as a tool to study the pharmacodynamics (PDs) of PAC1 receptor antagonists. The objectives of this first‐in‐human study were to: (1) determine the safety, tolerability, dose response, and time course of the dermal blood flow (DBF) changes after intradermal (i.d.) injections of maxadilan in the human forearm, and (2) assess the inter‐arm and inter‐period reproducibility of this response. This was a single‐center, open‐label study in healthy subjects, comprising three parts: (1) dose–response (n = 25), (2) response duration (n = 10), and (3) reproducibility (n = 15). DBF measurements were performed using laser Doppler imaging (LDI) up to 60 min postinjection, or up to 5 days for the response duration assessments. To assess reproducibility, the intraclass correlation coefficient (ICC) and sample sizes were calculated. The i.d. maxadilan (0.001, 0.01, 0.1, 0.9, 3, and 10 ng) produced a well‐tolerated, dose‐dependent increase in DBF, with a half‐maximal effective concentration fitted at 0.0098 ng. The DBF response to 0.9 ng maxadilan was quantifiable with LDI up to 72 h postinjection. The inter‐period reproducibility of the DBF response was better upon 0.9 ng (ICC > 0.6) compared to 0.01 ng (ICC
Databáze: Directory of Open Access Journals
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