人体成分分析在抗肿瘤药物药动学及毒性预测中的研究进展

Body composition analysis in pharmacokinetics and toxicity prediction of anticancer drugs

大多数抗肿瘤药物治疗窗较窄,给药剂量间较小的差异既可使一部分患者出现严重不良反应导致药物减量甚至治疗延迟,又可使一部分患者药物暴露相对不足,从而直接或间接的影响疾病结局。因此,任何以优化药物剂量为目的的探索都是值得的。依据BSA给药作为目前临床上抗肿瘤药物剂量标准化的经典方式,已成为多数细胞毒药物确定化疗剂量"约定俗成"的标准。但近年来这一传统的药物剂量计算方式饱受质疑^([1,2]):首先,BSA公式本身的推导及其在Ⅰ期临床试验以外的应用缺乏合理依据^([3]);此外,多项研究证实,依据BSA计算药物剂量并不能降低个体间药代动力学的差异^([4,5]),它带给大家一种错误的印象:即我们正在应用一个机体间特异性的度量指标来实现个体化给药。研究显示,人体成分与机体内药代动力学过程密切相关,人体成分分析作为人体组分及机能的评估手段能较好的预测抗肿瘤药物的毒性与疗效。随着BIA、CT等人体成分分析方法的飞速发展,基于人体成分分析计算药物剂量的相关研究已成为目前跨学科领域的热点课题。本文拟通过阐述人体成分与机体药代动力学的相关性及其对抗肿瘤药物毒性的预测作用,对目前人体成分分析在抗肿瘤药物剂量标准化临床转化过程中的相关研究作一综述。

Most anticancer drugs are characterised by a narrow therapeutic window; hence, a small change in dose can lead to poor antitumour effects or an unacceptable degree of toxicity, which may result in dose reductions and even delays and a poor prognosis. Therefore, any exploration aimed at optimizing the dosage of drugs is worthwhile. Classically cytotoxic chemotherapy has been dosed by adjusting doses by BSA. Recently, this traditional method of calculating the dose of drugs has been questioned. Firstly, the deduction of the BSA formula and its application outside the phase I clinical trial are lack of reasonable basis. In addition, a number of studies have demonstrated that BSA dosing is associated with high pharmacokinetic variability and failed to reduce interpatient variability. It gives the false impression that we are practicing personalized medicine by using a patient-specifc metric. According to the research, there is a close connection between body composition and the pharmacokinetics of anticancer agents which make the body composition as a prognostic factor of chemotherapy toxicity and outcome. With the rapid development of body composition analysis methods such as bioelectrical impedance analysis and computerized tomographic scanning, the research on drug dose calculation based on body composition analysis has become a hot issue in the interdisciplinary feld. In this paper, we aim to provide an overview about the relationships among the body composition, the pharmacokinetics and toxicity of anticancer agents, and the current research on body composition analysis in the clinical transformation process of dose standardization of anticancer agents is reviewed.