Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist.

Abstract

AIMS:

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy.

METHODS:

An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated.

RESULTS:

The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial.

CONCLUSIONS:

The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.

• Authors: Chi-Chung Li, Steve Vermeersch, William S Denney, William P Kennedy, John Palcza, Adrianna Gipson, Tae H Han, Rebecca Blanchard, Inge De Lepeleire, Marleen Depré, M Gail Murphy, Kristien Van Dyck, Jan N de Hoon
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 79 Issue 5 Pg. 831-7 (May 2015) ISSN: 1365-2125 [Electronic] England
• PMID: 25377933 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• 2-(8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro(4.5)dec-9-yl)-N-(2'-oxo-1,1',2',3-tetrahydrospiro(indene-2,3'-pyrrolo(2,3-b)pyridin)-5-yl)acetamide
• Bridged Bicyclo Compounds, Heterocyclic
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Spiro Compounds
• TRPV Cation Channels
• TRPV1 protein, human
• Capsaicin

Topics

• Administration, Oral
• Adolescent
• Adult
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, pharmacokinetics, pharmacology)
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Capsaicin (pharmacology)
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Healthy Volunteers
• Humans
• Male
• Models, Biological
• Predictive Value of Tests
• Skin (blood supply)
• Spiro Compounds (administration & dosage, pharmacokinetics, pharmacology)
• TRPV Cation Channels (antagonists & inhibitors)
• Vasodilation (drug effects)
• Young Adult