Characterization of Transit Times in the Large Intestine of Mice Following Treatment with a CGRP Antibody, CGRP Receptor Antibody and a Small Molecule CGRP Receptor Antagonist (1791)

Objective: Characterize the effects of a CGRP ligand antibody, a CGRP receptor antibody and a small molecule receptor antagonist, telcagepant, on gastrointestinal transport in mice. Background: Differences in the severity of constipation have been reported for CGRP modulating therapies following dosing for the preventive treatment of migraine. In order to further characterize this effect, charcoal meal transit times were quantified in mice following treatment with a variety of pharmacological agents. Transgenic mice expressing human RAMP1 in place of mouse RAMP1 of the CGRP receptor complex were utilized in order to replicate compound potency in humans. Design/Methods: The potency of the compounds to inhibit CGRP-stimulated formation of cAMP in a clonal cell line expressing human RAMP1 and rodent CLR was determined. The data from these experiments was used to select exposure levels of compounds for evaluation in the In vivo experiments that were pharmacologically relevant. Briefly, hRAMP1 mice were dosed with compound or control at appropriate time points prior to receiving a charcoal meal suspension via oral gavage. The mice were humanely euthanized at various times post-dose and the distance the charcoal meal had traveled in the large intestine was determined as an indicator of transit rates in the gastrointestinal system. Results: The CGRP receptor antibody inhibited GI transit in the large intestine. However, the CGRP ligand antibody did not have a significant effect. The small molecule CGRP receptor antagonist telcagepant also significantly inhibited gastrointestinal transit after acute dosing. Conclusions: Inhibition of gastrointestinal transit times in the large intestine of mice was observed with a CGRP receptor antibody and a small molecule CGRP receptor antagonist, in agreement with reported clinical data. In contrast, a CGRP ligand antibody did not inhibit transit times. The differences observed in this study may involve the ability of the CGRP ligand antibody to inhibit the effects of CGRP at both the CGRP and AMY1 receptors. Disclosure: Dr. Johnson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eli Lilly and Company. Dr. Johnson holds stock and/or stock options in Eli Lilly and Company, which sponsored research in which Dr. Johnson was involved as an investigator. Dr. Johnson holds stock and/or stock options in Eli Lilly and Company.Dr. Li has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eli Lilly and Company. Dr. Li holds stock and/or stock options in Eli Lilly and Company which sponsored research in which Dr. Li was involved as an investigator. Dr. Li holds stock and/or stock options in Eli Lilly and Company. Dr. Li has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eli Lilly and Company. Dr. Li holds stock and/or stock options in Eli Lilly and Company which sponsored research in which Dr. Li was involved as an investigator. Dr. Li holds stock and/or stock options in Eli Lilly and Company.