Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist.
OBJECTIVE
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.
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Chi-Chung
CC
Li
Steve
S
Vermeersch
William S
WS
Denney
William P
WP
Kennedy
John
J
Palcza
Adrianna
A
Gipson
Tae H
TH
Han
Rebecca
R
Blanchard
Inge
I
De Lepeleire
Marleen
M
Depré
M Gail
MG
Murphy
Kristien
K
Van Dyck
Jan N
JN
de Hoon
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008954:Models, Biological; D011237:Predictive Value of Tests; D012867:Skin / Q000098:blood supply*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D014664:Vasodilation / Q000187:drug effects*; D055815:Young Adult
C548781:2-(8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro(4.5)dec-9-yl)-N-(2'-oxo-1,1',2',3-tetrahydrospiro(indene-2,3'-pyrrolo(2,3-b)pyridin)-5-yl)acetamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D013141:Spiro Compounds; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002211:Capsaicin
CGRP; MK-3207; capsaicin; human; vasodilatation