Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist
| Autor: | Li, Chi-Chung, Vermeersch, Steve, Denney, William S, Kennedy, William P, Palcza, John, Gipson, Adrianna, Han, Tae H, Blanchard, Rebecca, De Lepeleire, Inge, Depré, Marleen, Murphy, M Gail, Van Dyck, Kristien, de Hoon, Jan N |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Cross-Over Studies Adolescent Dose-Response Relationship Drug Administration Oral TRPV Cation Channels Bridged Bicyclo Compounds Heterocyclic Models Biological Healthy Volunteers Vasodilation Young Adult Double-Blind Method Calcitonin Gene-Related Peptide Receptor Antagonists Predictive Value of Tests Humans Pk-Pd Relationships Spiro Compounds Capsaicin Skin |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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