부산대학교 도서관

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 ( E C50 of 1.59 n m) 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. [ABSTRACT FROM AUTHOR]