Abstract：
Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer\'s portfolio (PFE-1 and PFE-2, respectively) that induced renal tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, ii) Phase 2 rheumatoid arthritis patients (RA; n = 266) dosed with PFE-2, iii) lupus patients on standard-of-care therapies (n = 121), and iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.
摘要：
药物性肾损伤（DIKI）是一个重要的问题，在药物开发和临床实践中。我们报告了一种以患者为中心的方法，用于FDA合格的肾脏安全生物标志物小组的临床实施。在大鼠毒性研究中，重点介绍了辉瑞公司投资组合（分别为PFE-1和PFE-2）中诱导肾小管损伤的候选疗法的1期和2期试验。Clusterin(CLU)，胱抑素C(CysC),肾损伤分子-1（KIM-1），N-乙酰-β-D-氨基葡萄糖苷酶（NAG），中性粒细胞明胶酶相关脂质运载蛋白（NGAL），和骨桥蛋白（OPN）的尿液样本中的测量来自i）1期健康志愿者（HV；n=12）服用PFE-1，ii）2期类风湿关节炎患者（RA；n=266）服用PFE-2，iii）接受标准治疗的狼疮患者（n=121），和iv)健康志愿者(n=60)。FDA定义的复合措施(CM)，计算为6个生物标志物的几何平均响应，相对于安慰剂，服用100毫克PFE-1的HV增加了30%，提供DIKI的证据。相比之下,服用PFE-2的RA患者的CM与安慰剂对照相当，有助于降低临床相关剂量对DIKI的关注风险。比较不同疾病状态的个体生物标志物浓度显示，CLU，KIM-1NAG,NGAL,和OPN在RA和狼疮患者(没有严重的活动性狼疮性肾炎的患者)的尿中相对于HVs升高。总的来说,这些案例研究证明了使用FDA合格的肾脏生物标志物小组指导风险评估的价值，剂量选择,以及新疗法的临床决策，在HV和患者人群中。
