了解顺铂药代动力学和毒效学,预测和预防肾损伤。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Lauren E Thompson, Melanie S Joy
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引用次数: 0

摘要

顺铂是一种常见的铂类化疗药物,约有 30% 的患者会诱发急性肾损伤 (AKI)。顺铂诱发急性肾损伤的药代动力学/毒效学(PKTD)模型已被用于了解风险因素和评估潜在的缓解策略。虽然传统的肾功能临床生物标记物[如血清肌酐 (SCr)、血尿素氮 (BUN)、估计肾小球滤过率 (eGFR) 和肌酐清除率 (CrCl)]和较新的肾损伤亚临床生物标记物[如尿液肾损伤分子 1]都可以用于评估顺铂诱导的 AKI。尿肾损伤分子 1 (KIM-1)、β-2 微球蛋白 (B2M)、中性粒细胞明胶酶相关脂联素 (NGAL)、钙巴林蛋白等]可用于检测顺铂诱导的 AKI,但已发表的 PKTD 模型仅限于使用传统的临床生物标记物。以前确定的顺铂肾毒性风险因素包括剂量、年龄、性别、种族、体表面积、遗传学、伴随药物和合并症。然而,铂的浓度和 PK 与肾损伤生物标志物之间的关系尚未得到很好的阐明。本综述讨论了在临床研究、小鼠模型和体外模型中对顺铂诱导的肾毒性的评估,并研究了现有的人体 PK 和 TD 数据。在已确定的风险因素存在的情况下,加深对铂类 PK 和 TD 之间关系的了解将有助于预测和预防顺铂肾损伤。意义声明 由于顺铂治疗仍会导致三分之一的患者发生肾损伤,因此进一步了解传统临床和当代亚临床肾损伤 TD 标记所评估的铂 PK 与肾毒性之间的关系至关重要。不断发展的 PKTD 模型将有助于预测和预防顺铂诱导的肾毒性,这些模型结合了肾损伤生物标志物,提高了灵敏度,并包含了可能影响顺铂诱导的 AKI 发病风险的协变量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Understanding Cisplatin Pharmacokinetics and Toxicodynamics to Predict and Prevent Kidney Injury.

Cisplatin is a common platinum-based chemotherapeutic that induces acute kidney injury (AKI) in about 30% of patients. Pharmacokinetic/toxicodynamic (PKTD) models of cisplatin-induced AKI have been used to understand risk factors and evaluate potential mitigation strategies. While both traditional clinical biomarkers of kidney function [e.g. serum creatinine (SCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl)] and newer subclinical biomarkers of kidney injury [e.g. urinary kidney injury molecule 1 (KIM-1), beta-2 microglobulin (B2M), neutrophil gelatinase-associated lipocalin (NGAL), calbindin, etc.] can be used to detect cisplatin-induced AKI, published PKTD models are limited to using only traditional clinical biomarkers. Previously identified risk factors for cisplatin nephrotoxicity have included dose, age, sex, race, body surface area, genetics, concomitant medications, and comorbid conditions. However, the relationships between concentrations and PK of platinum and biomarkers of kidney injury have not been well elucidated. This review discusses the evaluation of cisplatin-induced nephrotoxicity in clinical studies, mouse models, and in vitro models, and examines the available human PK and TD data. Improved understanding of the relationships between platinum PK and TD, in the presence of identified risk factors, will enable the prediction and prevention of cisplatin kidney injury. Significance Statement As cisplatin treatment continues to cause AKI in a third of patients, it is critical to improve the understanding of the relationships between platinum PK and nephrotoxicity as assessed by traditional clinical and contemporary subclinical TD markers of kidney injury. Prediction and prevention of cisplatin-induced nephrotoxicity will be advanced by the evolving development of PKTD models that incorporate kidney injury biomarkers with enhanced sensitivity and include covariates that can impact risk of developing cisplatin-induced AKI.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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