Vu Thuy, Ma Peiming, Chen Jiyun Sunny, de Hoon Jan, Van Hecken Anne, Yan Lucy, Wu Liviawati Sutjandra, Hamilton Lisa, Vargas Gabriel
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320-1799, USA.
Clinical Pharmacology, GSK R&D, Shanghai, China.
Pharm Res. 2017 Sep;34(9):1784-1795. doi: 10.1007/s11095-017-2183-6. Epub 2017 Jun 7.
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.
辣椒素诱导的皮肤血流量（CIDBF）是一种经过验证的生物标志物，用于评估潜在的降钙素基因相关肽阻断疗法对偏头痛的靶点结合情况。为了表征依瑞奈尤单抗（AMG 334）的药代动力学（PK）并量化其对CIDBF的抑制作用，我们汇总了健康受试者和偏头痛受试者的单剂量和多剂量研究中的CIDBF数据。
进行重复的辣椒素激发试验和皮肤血流量测量，并测定血清依瑞奈尤单抗浓度。使用非线性混合效应建模方法进行群体分析。评估体重、性别和年龄对模型参数的影响。
假设依瑞奈尤单抗在中央室结合的二室靶点介导药物处置（TMDD）模型最能描述依瑞奈尤单抗的非线性PK。皮下吸收半衰期为1.6天，生物利用度为74%。依瑞奈尤单抗产生的最大抑制率为89%（95%置信区间：87-91%）。最大抑制率的50%和99%所需的依瑞奈尤单抗浓度分别为255 ng/mL和1134 ng/mL。体重增加与依瑞奈尤单抗清除率增加相关，但对CIDBF的抑制作用无影响。
我们的结果表明，依瑞奈尤单抗的药代动力学以TMDD模型最为特征，并导致对CIDBF的有效抑制。
