Chen Li, Lucas Andrew T, Mansfield Aaron S, Lheureux Stephanie, O'Connor Claire, Zamboni Beth A, Patel Kashish, McKee Tawnya, Moscow Jeffrey, Zamboni William C
UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, and UNC Advanced Translational Pharmacology and Analytical Chemistry Lab at University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Mayo Clinic, Rochester, Minnesota, USA.
Clin Transl Sci. 2025 Mar;18(3):e70178. doi: 10.1111/cts.70178.
Anetumab ravtansine, like other ADC drugs, has high inter-patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.
与其他抗体药物偶联物（ADC）一样，安奈单抗雷伐他汀在患者的药代动力学（PK）和药效学（PD）结果方面存在较高的个体间变异性，这引发了人们对当前给药方案是否对患者最优的担忧。本研究的目的是评估可能影响安奈单抗雷伐他汀PK和PD的协变量，尤其是身体形态和先天免疫系统（IIS），这是两项针对卵巢癌和间皮瘤患者的临床试验的一部分。分析了IIS细胞上Fcγ受体（FcγR）CD64的生物标志物、总体重（TBW）、体表面积（BSA）以及其他协变量，如性别和年龄，以确定它们与安奈单抗雷伐他汀PK的相关性。较高的FcγR CD64、TBW和BSA与安奈单抗雷伐他汀较高的清除率（CL）相关（p<0.05）。然而，TBW或BSA与FcγR CD64之间没有关系。女性患者的安奈单抗雷伐他汀CL（0.030±0.007L/h）低于男性患者（0.042±0.006L/h）（p<0.05）。在两项研究中，疾病稳定（SD）和部分缓解（PR）的患者与疾病进展（PD）的患者相比，安奈单抗雷伐他汀的AUC更高。仅基于TBW来个体化安奈单抗雷伐他汀以及可能其他ADC的剂量并不理想，而基于纳入IIS生物标志物、身体形态和性别的新指标来精确给药ADC可能更适合减少PK暴露的变异性、降低毒性并改善反应。
