Activation of PAC1 by maxadilan: a new human target engagement biomarker
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1
Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium
Background: Maxadilan, isolated from the sand fly Lutzomyia longipalpis, is a potent vasodilator peptide activating the
mammalian PAC1 receptor, a promising target for migraine therapy (1). Therefore, maxadilan is suggested as a target-engagement
tool to study PAC1 antagonists.
Objectives: (1) To determine, as a first in human study, the dose response, safety and time course of the dermal blood flow
(DBF) after intradermal (ID) injections of maxadilan in the human forearm and (2) to assess the inter-arm and inter-period
reproducibility of this response, as measured with Laser Doppler Imaging (LDI).
Results: Maxadilan was found to be safe based on AE reporting, ECG, vital signs, physical examination and safety laboratory
assessments. ID maxadilan (0.9, 3 and 10ng) produced a robust increase in DBF compared to baseline and placebo. Forearm
DBF response to 0.9ng ID injections of maxadilan in healthy male volunteers was reproducible between periods (Concordance
correlation coefficient (CCC)>0.7) and between arms (CCC>0.7) when data were calculated as AUC0-180min (perfusion
units*min). An increase in DBF was observed already 5 minutes after maxadilan injection and reached a plateau-phase after 60
minutes lasting until 72 hours, with an unexpected peak at 24 hours, compared to baseline and placebo. Sample size calculations
show that samples of approximately 10 subjects are sufficient to detect a 50% difference between 2 independent groups with
80% power.
Conclusion: As intradermal injections of maxadilan induce reproducible changes in dermal blood flow, it is an appealing new
target-engagement biomarker for the study of PAC1 receptor antagonists in early clinical development studies.
References:
1. Lerner EA, Iuga AO, Reddy VB. Maxadilan, a PAC1 receptor agonist from sand flies. Peptides 2007 28: 1651-4.
Keywords:
PAC1,
Phase I,
Maxadilan,
target engagement biomarker
Conference:
EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017.
Presentation Type:
Oral and Poster
Topic:
EUFEMED 2017 CONFERENCE
Citation:
Buntinx
L,
Depre
M,
Ampe
E,
Vanhecken
A and
De Hoon
J
(2019). Activation of PAC1 by maxadilan: a new human target engagement biomarker.
Front. Pharmacol.
Conference Abstract:
EUFEMED 2017.
doi: 10.3389/conf.fphar.2017.62.00008
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Received:
29 Aug 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Dr. Linde Buntinx, Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium, linde.buntinx@uzleuven.be