Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist |
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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 |
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Affiliation: | 1.Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA;2.Center for Clinical Pharmacology, University Hospitals Leuven & Department of Pharmaceutical and Pharmacological Sciences, KU Leuven;3.Merck Research Laboratories, MSD Europe, Brussels, Belgium |
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Abstract: | AimsCalcitonin 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.MethodsAn 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.ResultsThe 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.ConclusionsThe 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. |
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Keywords: | capsaicin CGRP human MK-3207 vasodilatation |
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