Inhibition of capsaicin‐induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK‐0974)

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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. WHAT THIS STUDY ADDS• 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. AIMSTo 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. METHODSA 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 mg capsaicin per 20 ml 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 capsaicininduced increase in DBF. RESULTSGeometric 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 EC90 for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nM. CONCLUSIONSTelcagepant 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.

Pharmacologic Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody against the Calcitonin Gene-Related Peptide Receptor

“…These results indicate that a halfmaximal in vivo effect is achieved at unbound plasma concentrations that are approximately twofold in excess of the in vitro IC 50 . When similarly evaluated in humans, telcagepant reduced the capsaicin-induced effect at an IC 50 of 101 nM total or 4 nM unbound (Sinclair et al, 2010), a similar approximately 2-fold in excess of the in vitro IC 50 , supporting the clinical translatability of this pharmacodynamic model. This was also true when evaluating the nearmaximal effect in NHP relative to humans.…”

Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model

“…In the case of CGRP 8-37 , it was suggested that this is due to its relatively lower affinity. The small molecules previously tested in this assay (MK-3207 and telcagepant) displayed higher affinity to CGRP-R than CGRP 8-37 , but still did not block the DBF response completely (Sinclair et al, 2010;Li et al, 2014). Mediators, such as nitric oxide, substance P, and prostaglandins, were previously excluded from playing a significant role in the capsaicin assay (Van der Schueren et al, 2008).…”

“…We have previously reported the inhibition of capsaicininduced DBF in the rat using LY2951742 (Benschop et al, 2014). A similar method has been used by others to assess the target engagement of small molecule inhibitors of the CGRP receptor in the periphery in both preclinical (Hershey et al, 2005;Salvatore et al, 2008) and clinical (Salvatore et al, 2010;Sinclair et al, 2010) settings. Both LSN2915644 and LY2951742 antibodies bind CGRP with high affinity (10 and 31 pM, respectively; R. J.…”

“…Nevertheless, LY2951742 exhibits comparable maximal inhibition of capsaicin-induced DBF as telcagepant, a CGRP-R antagonist that showed efficacy in phase 3 migraine clinical trials at doses that inhibited capsaicin-induced DBF (Ho et al, 2008;Sinclair et al, 2010).…”

“…The capsaicin-induced DBF change can be quantified using laser Doppler imaging (LDI), and CGRP was identified as the key mediator involved in this model (Van der Schueren et al, 2008). This neurogenic inflammation model, therefore, can be used to evaluate the target engagement of compounds that inhibit the CGRP pathway both preclinically (Salvatore et al, 2008;Benschop et al, 2014) and in clinical development (Salvatore et al, 2010;Sinclair et al, 2010).…”