Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model

被引:43
|
作者
Vermeersch, Steve [1 ,2 ]
Benschop, Robert J. [3 ]
Van Hecken, Anne [1 ,2 ]
Monteith, David [3 ]
Wroblewski, Victor J. [3 ]
Grayzel, David [4 ]
de Hoon, Jan [1 ,2 ]
Collins, Emily C. [3 ]
机构
[1] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Ctr Clin Pharmacol, Leuven, Belgium
[2] Univ Hosp Leuven, Leuven, Belgium
[3] Eli Lilly & Co, Indianapolis, IN 46285 USA
[4] Atlas Venture, Cambridge, MA USA
来源
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2015年 / 354卷 / 03期
关键词
CGRP RECEPTOR ANTAGONIST; BINDING-SITES; MIGRAINE; LOCALIZATION; BIBN4096BS; NEURONS; POTENT; PAIN;
D O I
10.1124/jpet.115.224212
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.
引用
收藏
页码:350 / 357
页数:8
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