Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, USA.
Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA.
J Pharmacokinet Pharmacodyn. 2020 Jun;47(3):255-266. doi: 10.1007/s10928-020-09688-y. Epub 2020 Apr 25.
A population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model. The data included single and multiple dosing of intravenous and subcutaneous BIIB059. BDCA2 internalization (PD marker) was measured for all subjects by monitoring reduction of BDCA2 on pDC cell surface and used for development of the popPD model. A two-compartment popPK model with linear plus non-linear elimination was found to best describe BIIB059 PK. BDCA2 levels were best captured using an indirect response model with stimulation of the elimination of BDCA2. Clearance in SLE subjects was 25% higher compared to HV (6.87 vs 5.52 mL/h). Bodyweight was identified as only other covariate on clearance and central volume. The estimates of EC and E were 0.35 μg/mL and 8.92, respectively. No difference in EC and E was observed between SLE and HV. The popPK/PD model described the data accurately, as evaluated by pcVPCs and bootstrap. The presented popPK/PD model for BIIB059 provides valuable insight into the dynamics and dose-response relationship of BIIB059 for the treatment of SLE and CLE and was used to guide dose selection for the Phase 2 clinical study (NCT02847598).
BIIB059（抗血树突状细胞抗原 2 [抗-BDCA2]）是一种人源化 IgG1 单克隆抗体，目前正在开发用于治疗系统性红斑狼疮（SLE）和皮肤白细胞碎裂性血管炎（CLE），本文建立了该药物的群体药代动力学/药效动力学（popPK/PD）模型。BIIB059 与 BDCA2 结合，BDCA2 是一种浆细胞样树突状细胞（pDC）特异性受体，当与配体结合时，可抑制 IFN-I 和其他炎症介质的产生。本研究利用健康成年志愿者（HV，n=87）和 SLE 患者（n=22）的 1 期 PK 和 PD 数据，建立了 popPK/PD 模型。这些数据包括静脉和皮下注射 BIIB059 的单剂量和多剂量。通过监测 pDC 细胞表面 BDCA2 的减少，对所有受试者进行 BDCA2 内化（PD 标志物）测量，用于 popPD 模型的建立。结果显示，二室 popPK 模型加线性和非线性消除，能最好地描述 BIIB059 的 PK。使用间接反应模型，刺激 BDCA2 的消除，可最佳地描述 BDCA2 水平。与 HV 相比，SLE 患者的清除率高 25%（6.87 比 5.52 mL/h）。体重被确定为清除率和中央容积的唯一其他协变量。EC 和 E 的估计值分别为 0.35 μg/mL 和 8.92。SLE 和 HV 之间，EC 和 E 没有差异。PCVPCs 和 bootstrap 评估表明，popPK/PD 模型准确地描述了数据。该模型为 BIIB059 治疗 SLE 和 CLE 的动力学和剂量反应关系提供了有价值的见解，并用于指导 2 期临床研究（NCT02847598）的剂量选择。
