The potent calcitonin gene‐related peptide receptor antagonist, telcagepant, does not affect nitroglycerin‐induced vasodilation in healthy men

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT WHAT THIS STUDY ADDS• This study shows that telcagepant, at a supra-therapeutic dose for the treatment of acute migraine headache, has no clinically relevant effect on NTG-induced haemodynamic changes in healthy male volunteers. There is also no measurable vasoconstrictor effect of telcagepant as such in both the central and peripheral vascular bed. The results of the present study support the favourable cardiovascular safety profile of telcagepant and indicate that CGRP is not involved in NTG-induced vasodilation in humans. AIMSTo assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). METHODSTwenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI). RESULTSThe aortic AIx following NTG decreased by -18.50 (-21.02, -15.98) % after telcagepant vs. -17.28 (-19.80, -14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated. CONCLUSIONSTelcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.

Effect of Telcagepant on Spontaneous Ischemia in Cardiovascular Patients in a Randomized Study

“…The present findings are in line with preclinical data, 10‐15 and findings in healthy human subjects 16‐18 suggesting that CGRP receptor antagonism does not have direct vasoconstrictive effects. There are a number of limitations to the interpretation of the present data.…”

“…In dogs, CGRP 8‐37 did not influence hemodynamics after induction of congestive heart failure, 13 the severity of myocardial ischemia, 14 or the reactive hyperemic response to brief coronary occlusion 15 . In healthy humans, telcagepant had no effect on peripheral hemodynamics, 16 24‐hour mean ambulatory blood pressure and heart rate, 17 or nitroglycerin‐induced vasolidation 18 . Thus, antagonism of CGRP may potentially allow for treatment of migraine in patients with coronary artery disease.…”

Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

“…The BAD fold increase following NTG was 1.14 after telcagepant vs 1.13 after placebo. No vasoconstrictor effect of telcagepant could be demonstrated …”

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

“…Early human experiments were conducted by Petersen and colleagues, who showed clinically that low doses of the CGRP‐RA olcegepant completely inhibited headache induced by CGRP, yet at supratherapeutic doses there was no effect on blood pressure, the diameter of systemic or cerebral arteries, or cerebral blood flow . Clinically, studies with telcagepant (MK‐0974) showed that it had no effect on spontaneous ischemia in cardiovascular patients, that it did not affect exercise time at supratherapeutic doses in patients with stable angina, that it did not affect nitroglycerin‐induced vasodilation in healthy men, nor was there any hemodynamic interaction with sumatriptan . A partially completed study of supratherapeutic doses of telcagepant (600 and 900 mg) in patients with migraine and stable coronary artery disease also supported the cardiovascular safety of the CGRP receptor antagonist mechanism …”