降钙素基因相关肽单克隆抗体LY2951742在辣椒素诱导的皮肤血流模型中的转化药效学
Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model.
作者信息
Vermeersch Steve, Benschop Robert J, Van Hecken Anne, Monteith David, Wroblewski Victor J, Grayzel David, de Hoon Jan, Collins Emily C
机构信息
Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.)
出版信息
J Pharmacol Exp Ther. 2015 Sep;354(3):350-7. doi: 10.1124/jpet.115.224212. Epub 2015 Jun 26.
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.
LY2951742是一种靶向降钙素基因相关肽（CGRP）的单克隆抗体，目前正用于偏头痛预防和骨关节炎疼痛的治疗研发。为支持LY2951742的临床开发，辣椒素诱导的皮肤血流（DBF）被用作一种靶点结合生物标志物，以评估非人类灵长类动物和健康志愿者体内的CGRP活性。用激光多普勒成像测量，在单次静脉注射CGRP抗体后，非人类灵长类动物中辣椒素诱导的DBF抑制呈剂量依赖性，且至少持续29天。这些信息被用于建立一个药代动力学/药效学模型，该模型正确预测了从单次皮下注射5毫克剂量开始，人类体内辣椒素诱导的DBF抑制情况。正如预期的那样，随着LY2951742血浆浓度升高，辣椒素诱导的DBF抑制程度增加。在I期研究中收集的药代动力学数据与这种药效学生物标志物的结合，提供了剂量反应关系，有助于LY2951742 II期临床开发的剂量选择。
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