Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974).
BACKGROUND
* Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. * CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. * A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm.


CONCLUSIONS
* This study shows that the novel oral CGRP receptor antagonist, telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. * This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.


OBJECTIVE
To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine.


METHODS
A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of telcagepant 300 mg, telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 microg capsaicin per 20 microl water-ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before ('baseline'), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF.


RESULTS
Geometric mean plasma concentrations after dosing with 300 mg and 800 mg telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC(90) for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm.


CONCLUSIONS
Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.
Sinclair
Simon R
SR
Merck Research Laboratory, Upper Gwynedd, PA, USA. simon_sinclair@merck.com
Kane
Stefanie A
SA
Van der Schueren
Bart J
BJ
Xiao
Alan
A
Willson
Kenneth J
KJ
Boyle
Janet
J
de Lepeleire
Inge
I
Xu
Yang
Y
Hickey
Lisa
L
Denney
William S
WS
Li
Chi-Chung
CC
Palcza
John
J
Vanmolkot
Floris H M
FH
Depré
Marleen
M
Van Hecken
Anne
A
Murphy
M Gail
MG
Ho
Tony W
TW
de Hoon
Jay N
JN
D000284:Administration, Oral; D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D001381:Azepines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012039:Regional Blood Flow / Q000187:drug effects*; D012867:Skin / Q000098:blood supply*; D014665:Vasodilator Agents / Q000494:pharmacology*; D055815:Young Adult
D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D014665:Vasodilator Agents; C525458:telcagepant; D002211:Capsaicin