Yao Xueting, Ren Yupeng, Zhao Qian, Chen Xia, Jiang Ji, Liu Dongyang, Hu Pei
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100032, China; Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Pking Union Medical College Hospital, Beijing 100032, China; Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China.
Johnson & Johnson Pharmaceuticals (Shanghai) Ltd., Shanghai 200240, China.
Eur J Pharm Sci. 2021 Apr 1;159:105704. doi: 10.1016/j.ejps.2021.105704. Epub 2021 Jan 10.
RC18 is a novel recombinant fusion protein targeting on B lymphocyte stimulator (BLyS). We aimed to develop and qualify a population pharmacokinetics (PopPK) model for RC18 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process.
A TMDD model of RC18 was developed using data from two phase I clinical trial (n = 23). The TMDD structural model was developed by simultaneous fitting of the serum free RC18 and serum RC18-BLyS complex. Potential covariates were screened using stepwise method, and predictive performance was qualified using a prediction-corrected visual predictive check (pcVPC) and bootstrap.
A two compartment TMDD model with first order absorption for subcutaneous administration was built. The final model included a significant relationship between distribution volume of the central compartment and body weight. And the baseline of immunoglobulin IgG had significant effect on the baseline of target BLyS. The plots from goodness-of-fit and pcVPC confirmed good predictive performance of this TMDDmodel.
This mechanistic TMDD model integrated the interaction of RC18 with its target BLyS and accurately predicts both RC18 and RC18-BLyS complex profiles in RA and SLE patients. Simulated target change profiles can be used to help guide rational dose regimen selection and used as a biomarker for efficacy evaluation.
RC18是一种新型的靶向B淋巴细胞刺激因子（BLyS）的重组融合蛋白。我们旨在建立并验证系统性红斑狼疮（SLE）和类风湿关节炎（RA）患者中RC18的群体药代动力学（PopPK）模型，同时考虑其机制性靶点介导的药物处置（TMDD）过程。
利用两项I期临床试验（n = 23）的数据建立了RC18的TMDD模型。通过同时拟合游离RC18血清和RC18 - BLyS血清复合物来建立TMDD结构模型。采用逐步法筛选潜在的协变量，并通过预测校正视觉预测检查（pcVPC）和自抽样法验证预测性能。
建立了皮下给药具有一级吸收的二室TMDD模型。最终模型包括中央室分布容积与体重之间的显著关系。免疫球蛋白IgG的基线对靶点BLyS的基线有显著影响。拟合优度图和pcVPC图证实了该TMDD模型具有良好的预测性能。
该机制性TMDD模型整合了RC18与其靶点BLyS的相互作用，能够准确预测RA和SLE患者中RC18和RC18 - BLyS复合物的情况。模拟的靶点变化情况可用于指导合理的给药方案选择，并作为疗效评估的生物标志物。
