Winning Alex, Sietsema William K, Buck Kristen K, Linsmeier Abigail, Wiczling Pawel
Department of Pharmacometrics Modeling, A2-Ai LLC, Ann Arbor, MI, USA.
Research and Development, Lisata Therapeutics, Inc., Basking Ridge, NJ, USA.
Clin Pharmacol Drug Dev. 2025 Mar;14(3):240-251. doi: 10.1002/cpdd.1502. Epub 2025 Jan 9.
Certepetide (aka LSTA1 and CEND-1) is a novel cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide being developed to treat solid tumors. Certepetide is designed to overcome existing challenges in treating solid tumors by delivering co-administered anticancer drugs into the tumor while selectively depleting immunosuppressive T cells, enhancing cytotoxic T cells in the tumor microenvironment, and inhibiting the metastatic cascade. A population pharmacokinetic (PK) analysis was conducted to characterize the concentration-time profile of patients with metastatic exocrine pancreatic cancer receiving certepetide in combination with nab-paclitaxel and gemcitabine, and to investigate the effects of clinically relevant covariates on PK parameters. The PK of certepetide was characterized by a 2-compartment model with linear elimination and a proportional residual error structure. Body weight and baseline creatinine clearance (CrCL) were found to have statistically significant effects on central and peripheral volume (Vc and Vp) and clearance (CL) parameters, respectively, during model development and were included as covariate effects in the final PK model. Forest plots demonstrated a potentially clinically meaningful impact of high body weight (100 kg) on certepetide exposure (steady-state maximum concentration [C] and area under the concentration-time curve [AUC]), as well as low and high CrCL (50 and 150 mL/min) on AUC. Exposure predictions illustrated a relationship between certepetide exposure (AUC) and renal function, with increasing exposure and decreasing CL of certepetide observed with worsening renal function. Modeling will strengthen the understanding of certepetide's PKs and will inform dose optimization in ongoing drug development activities.
Certepetide（又名LSTA1和CEND-1）是一种新型的环状肿瘤靶向内化精氨酰甘氨酰天冬氨酸肽，正在开发用于治疗实体瘤。Certepetide旨在通过将联合使用的抗癌药物输送到肿瘤中，同时选择性地消耗免疫抑制性T细胞、增强肿瘤微环境中的细胞毒性T细胞以及抑制转移级联反应，来克服治疗实体瘤中存在的挑战。进行了群体药代动力学（PK）分析，以表征转移性外分泌胰腺癌患者接受Certepetide联合纳米白蛋白结合型紫杉醇和吉西他滨时的浓度-时间曲线，并研究临床相关协变量对PK参数的影响。Certepetide的PK特征为具有线性消除和比例残差误差结构的二室模型。在模型开发过程中，发现体重和基线肌酐清除率（CrCL）分别对中央室和外周室容积（Vc和Vp）以及清除率（CL）参数有统计学显著影响，并作为协变量效应纳入最终的PK模型。森林图显示高体重（100 kg）对Certepetide暴露（稳态最大浓度[C]和浓度-时间曲线下面积[AUC]）具有潜在的临床意义，低CrCL和高CrCL（50和150 mL/min）对AUC也有影响。暴露预测表明Certepetide暴露（AUC）与肾功能之间存在关系，随着肾功能恶化，观察到Certepetide的暴露增加而CL降低。建模将加强对Certepetide药代动力学的理解，并为正在进行的药物开发活动中的剂量优化提供依据。
