Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
Eli Lilly and Company, Indianapolis, Indiana, USA.
Clin Pharmacol Drug Dev. 2021 May;10(5):440-452. doi: 10.1002/cpdd.929. Epub 2021 Mar 19.
Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was recently approved for migraine prophylaxis. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between galcanezumab concentration and inhibition of capsaicin-induced dermal blood flow (CIDBF) was evaluated using first-in-human data following 6 single subcutaneous doses (1 to 600 mg) or multiple (4) 150-mg doses every 2 weeks in 7 cohorts (7 actively treated subjects and 2 placebo-treated healthy subjects). Galcanezumab pharmacokinetics were best described by a 1-compartment model with delayed first-order absorption/linear elimination. Apparent estimates (between-subject variability) of clearance, volume of distribution, absorption rate constant, and lag time were 0.0106 L/h (27%CV), 11.2 L (21%CV), 0.0192 h (89%CV), and 0.202 hours, respectively. Estimated elimination half-life was about 30 days. An effect compartment link model described the concentration-effect relationship; estimated maximum inhibitory effect was 70.5%, and 50% maximum inhibitory effect concentration (IC ) was 1060 ng/mL. Galcanezumab showed dose- and concentration-dependent potent and durable inhibition of CIDBF. Simulated effect compartment concentrations were maintained above IC after 12 weeks of dosing. Near-maximal CIDBF inhibition occurred with 150 mg biweekly for 12 weeks lasting ≥24 weeks or with ≥30 mg every 2 weeks or 195 mg every 13 weeks. Quantitative modeling of galcanezumab PK/PD supported dose selection for the phase 2 proof-of-concept study.
加兰他敏，一种针对降钙素基因相关肽的人源化单克隆抗体，最近被批准用于偏头痛预防。通过在 7 个队列（7 个接受积极治疗的受试者和 2 个接受安慰剂治疗的健康受试者）中进行的 6 次单皮下剂量（1 至 600 毫克）或 4 次每 2 周 150 毫克的首次人体数据，评估了加兰他敏浓度与辣椒素诱导的皮肤血流（CIDBF）抑制之间的药代动力学/药效学（PK/PD）关系。加兰他敏药代动力学最好用具有延迟一阶吸收/线性消除的 1 室模型来描述。清除率、分布容积、吸收速率常数和滞后时间的表观估计值（个体间变异性）分别为 0.0106 L/h（27%CV）、11.2 L（21%CV）、0.0192 h（89%CV）和 0.202 小时。估计消除半衰期约为 30 天。效应室链接模型描述了浓度-效应关系；估计最大抑制效应为 70.5%，50%最大抑制效应浓度（IC ）为 1060ng/mL。加兰他敏对 CIDBF 表现出剂量和浓度依赖性的强效和持久抑制作用。模拟效应室浓度在 12 周给药后仍维持在 IC 以上。CIDBF 抑制作用接近最大，每 2 周 150 毫克，持续 12 周，持续时间≥24 周，或每 2 周≥30 毫克，或每 13 周 195 毫克。加兰他敏 PK/PD 的定量建模支持了 2 期概念验证研究的剂量选择。
