A Mouse Diversity Panel Approach Reveals the Potential for Clinical Kidney Injury Due to DB289 Not Predicted by Classical Rodent Models
A Mouse Diversity Panel Approach Reveals the Potential for Clinical Kidney Injury Due to DB289 Not Predicted by Classical Rodent Models
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DOI：
10.1093/toxsci/kfs238
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发表时间：
2012-12-01
影响因子：
3.8
通讯作者：
Watkins, Paul B.
中科院分区：
文献类型：
--
作者：
Harrill, Alison H.;DeSmet, Kristina D.;Watkins, Paul B.
DB289是第一种临床试验显示对治疗非洲锥虫病(非洲昏睡病)有效的口服药物。轻微的肝脏毒性被注意到，但不是治疗的限制。然而，当几个接受治疗的受试者出现严重的肾脏损伤时，DB289的开发被终止，这一风险没有从临床前试验中预测出来。我们测试了这样的假设，即DB289的肾脏安全风险将在由34个遗传多样性近交系小鼠品系组成的小鼠多样性小组(MDP)中检测到。给MDP小鼠灌胃DB289或赋形剂10天后，测定血尿素氮(BUN)、血肌酐(SCr)及尿液中肾损伤标志物。在BUN和Scr保持在参考范围内的同时，观察到敏感品系小鼠尿中肾损伤分子-1(Kim-1)水平显著升高。Kim-1的升高与丙氨酸氨基转移酶(ALT)的升高并不总是一致的，这表明肾脏损伤与肝脏损伤无关。对Kim-1基因上调的全基因组关联分析表明，参与胆固醇和脂肪生物合成和运输、氧化应激和细胞因子释放的基因可能在DB289肾脏损伤中发挥作用。综上所述，这项研究的数据突出了使用MDP来预测临床相关毒性、识别可能转化为临床的相关毒性生物标记物以及确定潜在毒性机制的效用。此外，这项研究中鉴定的敏感小鼠品系可能有助于筛选肾脏损伤的下一类化合物。
DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing. We tested the hypothesis that the kidney safety liability of DB289 would be detected in a mouse diversity panel (MDP) comprised of 34 genetically diverse inbred mouse strains. MDP mice received 10 days of oral treatment with DB289 or vehicle and classical renal biomarkers blood urea nitrogen (BUN) and serum creatinine (sCr), as well as urine biomarkers of kidney injury were measured. While BUN and sCr remained within reference ranges, marked elevations were observed for kidney injury molecule-1 (KIM-1) in the urine of sensitive mouse strains. KIM-1 elevations were not always coincident with elevations in alanine aminotransferase (ALT), suggesting that renal injury was not linked to hepatic injury. Genome-wide association analyses of KIM-1 elevations indicated that genes participating in cholesterol and lipid biosynthesis and transport, oxidative stress, and cytokine release may play a role in DB289 renal injury. Taken together, the data resulting from this study highlight the utility of using an MDP to predict clinically relevant toxicities, to identify relevant toxicity biomarkers that may translate into the clinic, and to identify potential mechanisms underlying toxicities. In addition, the sensitive mouse strains identified in this study may be useful in screening next-in-class compounds for renal injury.