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

AbstractAIMS:
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.
AuthorsChi-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
JournalBritish journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 79 Issue 5 Pg. 831-7 (May 2015) ISSN: 1365-2125 [Electronic] England
PMID25377933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 The British Pharmacological Society.

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