Pharmacology of erenumab in human isolated coronary and meningeal arteries: Additional effect of gepants on top of a maximum effect of erenumab

TY - JOUR

T1 - Pharmacology of erenumab in human isolated coronary and meningeal arteries: Additional effect of gepants on top of a maximum effect of erenumab

AU - de Vries, Tessa

AU - Rubio-Beltrán, Eloísa

AU - van den Bogaerdt, Antoon

AU - Dammers, Ruben

AU - Danser, A. H. Jan

AU - Snellman, Josefin

AU - Bussiere, Jeanine

AU - MaassenVanDenBrink, Antoinette

N1 - Funding Information: TdV, ERB, AvdB, RD and AHJD declare no conflict of interest. JS is employed by Novartis. JB is employed by Amgen. AMvdB received personal fees (fees as advisor or speaker, consultancy, or any other) from Allergan‐Abbvie, Lilly, Novartis and Teva. She received research support from Novartis, Satsuma and Tonix, as well as independent research support from the Dutch Research Council and the Netherlands Organisation for Health Research and Development. Publisher Copyright: © 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

PY - 2024/6

Y1 - 2024/6

N2 - Background and Purpose: Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for migraine treatment. Here, the effect of the monoclonal antibody erenumab on CGRP-induced vasorelaxation was investigated in human isolated blood vessels, as well as the effect of combining erenumab with the small molecule drugs, namely rimegepant, olcegepant, or sumatriptan. Experimental Approach: Concentration–response curves to CGRP, adrenomedullin or pramlintide were constructed in human coronary artery (HCA) and human middle meningeal artery (HMMA) segments, incubated with or without erenumab and/or olcegepant. pA 2 or pK b values were calculated to determine the potency of erenumab in both tissues. To study whether acutely acting antimigraine drugs exerted additional CGRP-blocking effects on top of erenumab, HCA segments were incubated with a maximally effective concentration of erenumab (3 μM), precontracted with KCl and exposed to CGRP, followed by rimegepant, olcegepant, or sumatriptan in increasing concentrations. Key Results: Erenumab shifted the concentration-response curve to CGRP in both vascular tissues. However, in HCA, the Schild plot slope was significantly smaller than unity, whereas this was not the case in HMMA, indicating different CGRP receptor mechanisms in these tissues. In HCA, rimegepant, olcegepant and sumatriptan exerted additional effects on CGRP on top of a maximal effect of erenumab. Conclusions and Implications: Gepants have additional effects on top of erenumab for CGRP-induced relaxation and could be effective in treating migraine attacks in patients already using erenumab as prophylaxis.

AB - Background and Purpose: Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for migraine treatment. Here, the effect of the monoclonal antibody erenumab on CGRP-induced vasorelaxation was investigated in human isolated blood vessels, as well as the effect of combining erenumab with the small molecule drugs, namely rimegepant, olcegepant, or sumatriptan. Experimental Approach: Concentration–response curves to CGRP, adrenomedullin or pramlintide were constructed in human coronary artery (HCA) and human middle meningeal artery (HMMA) segments, incubated with or without erenumab and/or olcegepant. pA 2 or pK b values were calculated to determine the potency of erenumab in both tissues. To study whether acutely acting antimigraine drugs exerted additional CGRP-blocking effects on top of erenumab, HCA segments were incubated with a maximally effective concentration of erenumab (3 μM), precontracted with KCl and exposed to CGRP, followed by rimegepant, olcegepant, or sumatriptan in increasing concentrations. Key Results: Erenumab shifted the concentration-response curve to CGRP in both vascular tissues. However, in HCA, the Schild plot slope was significantly smaller than unity, whereas this was not the case in HMMA, indicating different CGRP receptor mechanisms in these tissues. In HCA, rimegepant, olcegepant and sumatriptan exerted additional effects on CGRP on top of a maximal effect of erenumab. Conclusions and Implications: Gepants have additional effects on top of erenumab for CGRP-induced relaxation and could be effective in treating migraine attacks in patients already using erenumab as prophylaxis.

KW - CGRP

KW - erenumab

KW - gepants

KW - migraine

KW - monoclonal antibodies

UR - http://www.scopus.com/inward/record.url?scp=85184436506&partnerID=8YFLogxK

U2 - 10.1111/bph.16322

DO - 10.1111/bph.16322

M3 - Article

SN - 0007-1188

VL - 181

SP - 1720

EP - 1733

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 12

ER -