Clinical Pharmacology & Pharmacometrics, Biogen Inc., Cambridge, Massachusetts, USA.
CPT Pharmacometrics Syst Pharmacol. 2020 Sep;9(9):515-522. doi: 10.1002/psp4.12538. Epub 2020 Aug 19.
This modeling and simulation analysis was aimed at selecting doses of cinpanemab (BIIB054), a monoclonal antibody targeting aggregated α-synuclein, for a phase II study in Parkinson's disease (PD). Doses and regimens were proposed based on anticipated target concentration in brain interstitial fluid (ISF); in vitro/in vivo data on the affinity of monoclonal antibodies to the target protein; and safety, tolerability, and pharmacokinetic data (1-135 mg/kg intravenous administration) from a phase I single ascending dose (SAD) study. A population pharmacokinetic modeling approach was used to select intravenous doses of 250, 1,250, and 3,500 mg every 4 weeks, to maintain 50%, 90%, and > 90% of target binding in ISF of PD participants. A favorable safety profile from the SAD study-which showed that cinpanemab was generally well-tolerated at doses up to 90 mg/kg, supported by modeling and simulations of the anticipated safety margins-allowed implementation of a fixed-dose approach.
本建模和模拟分析旨在为帕金森病（PD）的 II 期研究选择 cinpanemab（BIIB054）的剂量，该药是一种针对聚集的 α-突触核蛋白的单克隆抗体。根据预期的脑间质液（ISF）中目标浓度、单克隆抗体对目标蛋白的亲和力的体外/体内数据以及来自 I 期单次递增剂量（SAD）研究的安全性、耐受性和药代动力学数据（1-135mg/kg 静脉给药）来提出剂量和方案。采用群体药代动力学建模方法选择每 4 周静脉注射 250、1250 和 3500mg 的剂量，以维持 PD 参与者 ISF 中 50%、90%和>90%的目标结合。SAD 研究中的安全性概况良好——表明 cinpanemab 在高达 90mg/kg 的剂量下通常耐受良好，这得到了对预期安全边际的建模和模拟的支持——允许实施固定剂量方法。
