Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA.
J Pharmacokinet Pharmacodyn. 2024 Dec;51(6):905-917. doi: 10.1007/s10928-024-09941-8. Epub 2024 Sep 30.
Pozelimab, a monoclonal antibody directed against C5, is the first and only treatment for adult and pediatric patients (≥ 1 year) with CD55-deficient protein-losing enteropathy (CHAPLE) disease. A target-mediated drug disposition (TMDD) population pharmacokinetic (PopPK) model was developed using pooled data from four phase 1-3 studies to characterize the pharmacokinetics (PK) of total pozelimab and total C5, and to simulate free pozelimab and free C5 to support the dose regimen in patients with CHAPLE disease. A TMDD PopPK model was developed using total pozelimab and total C5 concentration-time data from 106 participants (82 healthy volunteers; 24 patients with paroxysmal nocturnal hemoglobinuria [PNH]). This model was refined and updated to include PK data from 10 patients with CHAPLE disease from a phase 2/3 study. Stochastic simulations predicted concentration-time profiles for total pozelimab, free pozelimab, and free C5, to obtain pozelimab exposure metrics for patients with CHAPLE disease. A two-compartment TMDD model with two binding sites based on the quasi-equilibrium approximation adequately described the concentration-time profiles of total pozelimab and total C5. Body weight was identified as the most important source of pozelimab PK variability; therefore, the dose was adjusted based on body weight for the predominantly pediatric patients with CHAPLE disease. A robust TMDD PopPK model was developed to describe the PK of total pozelimab and total C5 following pozelimab administration. Reliable predictions for individual exposures of total pozelimab and free C5 were possible and supported the 10 mg/kg weight-based dose regimen in patients with CHAPLE disease.
波泽利单抗是一种针对 C5 的单克隆抗体，是首个也是唯一一个治疗成人和儿科患者（≥1 岁）CD55 缺陷性蛋白丢失性肠病（CHAPLE）的药物。使用四项 I-III 期研究的汇总数据，开发了一种基于靶介导药物处置（TMDD）的群体药代动力学（PopPK）模型，以描述总波泽利单抗和总 C5 的药代动力学（PK），并模拟游离波泽利单抗和游离 C5，以支持 CHAPLE 疾病患者的剂量方案。使用来自 106 名参与者（82 名健康志愿者；24 名阵发性夜间血红蛋白尿 [PNH] 患者）的总波泽利单抗和总 C5 浓度-时间数据，开发了一种 TMDD PopPK 模型。该模型经过改进和更新，纳入了来自一项 II/III 期研究的 10 名 CHAPLE 疾病患者的 PK 数据。随机模拟预测了总波泽利单抗、游离波泽利单抗和游离 C5 的浓度-时间曲线，以获得 CHAPLE 疾病患者的波泽利单抗暴露指标。基于准平衡近似的两室 TMDD 模型，具有两个结合位点，可充分描述总波泽利单抗和总 C5 的浓度-时间曲线。体重被确定为波泽利单抗 PK 变异性的最重要来源；因此，对于以儿科患者为主的 CHAPLE 疾病患者，根据体重调整了剂量。开发了一种稳健的 TMDD PopPK 模型来描述波泽利单抗给药后总波泽利单抗和总 C5 的 PK。可以对总波泽利单抗和游离 C5 的个体暴露进行可靠预测，并支持 CHAPLE 疾病患者的 10mg/kg 体重为基础的剂量方案。
