Article date: May 2015
By: 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. Hoon, in Volume 79, Issue 5, pages 831-837
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.
DOI: 10.1111/bcp.12547
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