UCB Pharma, Slough, UK.
CPT Pharmacometrics Syst Pharmacol. 2022 Jan;11(1):116-128. doi: 10.1002/psp4.12739. Epub 2021 Nov 23.
Rozanolixizumab is a fully humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (mAb) that accelerates the removal of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibodies, via the natural lysosomal degradation pathway. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model characterizing the effect of rozanolixizumab on IgG levels in cynomolgus monkeys, translate it into humans to support the first-in-human (FIH) rozanolixizumab clinical trial study design, and, ultimately, develop a PK/PD model in humans. Simulations from the preclinical model were performed to predict IgG responses in humans and select clinically relevant doses in the FIH study. Good alignment was observed between predicted and observed reductions in IgG, which increased with increasing dose in the FIH study. The model successfully described the PK of the 4 and 7 mg/kg intravenous (i.v.) dose groups, although the PKs were underpredicted for the 1 mg/kg i.v. dose group. Updating the model with subsequent human data identified parameters that deviated from preclinical assumptions. The updated PK/PD model was able to effectively characterize the PK FcRn-IgG nonlinear system in response to rozanolixizumab in the FIH data.
罗沙诺利昔单抗是一种完全人源化的高亲和力抗人新生 Fc 受体（FcRn）单克隆抗体（mAb），通过天然溶酶体降解途径加速循环免疫球蛋白 G（IgG）的清除，包括致病性 IgG 自身抗体。本研究旨在开发一种药代动力学/药效学（PK/PD）模型，以描述罗沙诺利昔单抗对食蟹猴 IgG 水平的影响，将其转化为人类以支持首次人体（FIH）罗沙诺利昔单抗临床试验设计，并最终在人类中建立 PK/PD 模型。从临床前模型进行的模拟用于预测人类的 IgG 反应并选择 FIH 研究中具有临床相关性的剂量。在 FIH 研究中，观察到预测和观察到的 IgG 减少之间存在良好的一致性，随着剂量的增加，IgG 增加。该模型成功描述了 4 和 7mg/kg 静脉内（i.v.）剂量组的 PK，但 1mg/kg i.v.剂量组的 PK 被低估。使用随后的人类数据更新模型确定了与临床前假设不同的参数。更新后的 PK/PD 模型能够有效地描述 FIH 数据中罗沙诺利昔单抗对 FcRn-IgG 非线性系统的 PK。
