Thompson Lauren E, Joy Melanie S
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences (L.E.T., M.S.J.), University of Colorado Cancer Center (M.S.J.), and Division of Renal Diseases and Hypertension (M.S.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences (L.E.T., M.S.J.), University of Colorado Cancer Center (M.S.J.), and Division of Renal Diseases and Hypertension (M.S.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado.
J Pharmacol Exp Ther. 2024 Nov 19;391(3):399-414. doi: 10.1124/jpet.124.002287.
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 the pharmacokinetics (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 toxicodynamic (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.
顺铂是一种常见的铂类化疗药物，约30%的患者使用后会引发急性肾损伤（AKI）。顺铂诱导急性肾损伤的药代动力学/毒代动力学（PKTD）模型已被用于了解风险因素并评估潜在的缓解策略。虽然传统的肾功能临床生物标志物[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）]以及较新的肾脏损伤亚临床生物标志物[如尿肾损伤分子1（KIM-1）、β2微球蛋白（B2M）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、钙结合蛋白等]均可用于检测顺铂诱导的急性肾损伤，但已发表的PKTD模型仅限于使用传统的临床生物标志物。先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、合并用药和共病情况。然而，铂的浓度与药代动力学（PK）以及肾脏损伤生物标志物之间的关系尚未得到充分阐明。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，并审视了现有的人体PK和毒代动力学（TD）数据。在存在已确定的风险因素的情况下，更好地理解铂的PK与TD之间的关系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急性肾损伤，因此至关重要的是要更好地理解铂的PK与肾毒性之间的关系，这种关系可通过传统临床和当代肾脏损伤亚临床TD标志物来评估。将具有更高敏感性的肾脏损伤生物标志物与可能影响顺铂诱导的急性肾损伤发生风险的协变量纳入其中的PKTD模型的不断发展，将推动顺铂诱导的肾毒性的预测和预防。
