Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects.
Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects.
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DOI：
10.1007/s11095-017-2183-6
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发表时间：
2017-09
影响因子：
3.7
通讯作者：
Vargas G
中科院分区：
文献类型：
--
作者：
Vu T;Ma P;Chen JS;de Hoon J;Van Hecken A;Yan L;Wu LS;Hamilton L;Vargas G
辣椒素诱导的皮肤血流量（CIDBF）是一种经验证的生物标志物，用于评估潜在的降钙素基因相关肽阻断治疗偏头痛的目标参与。为了表征药代动力学（PK）并定量erenumab（AMG 334）对CIDBF的抑制作用，汇总了健康和偏头痛受试者单次和多次给药研究的CIDBF数据。重复进行辣椒素激发和DBF测量，并测定血清erenumab浓度。使用非线性混合效应建模方法进行群体分析。评价了体重、性别和年龄对模型参数的影响。假设erenumab在中央室中结合的二室靶向介导药物分布（TMDD）模型最佳描述了erenumab的非线性PK。皮下吸收半衰期为1.6天，生物利用度为74%。Erenumab产生的最大抑制率为89%（95%置信区间：87-91%）。50%和99%最大抑制所需的Erenumab浓度分别为255 ng/mL和1134 ng/mL。体重增加与erenumab清除率增加相关，但对CIDBF的抑制作用无影响。我们的结果表明，erenumab的药代动力学最好通过TMDD模型表征，并导致CIDBF的有效抑制。本文的在线版本（doi：10.1007/s11095-017-2183-6）包含补充材料，可供授权用户使用。
Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated. Two-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87–91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF. Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF. The online version of this article (doi:10.1007/s11095-017-2183-6) contains supplementary material, which is available to authorized users.
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