药物性肝损伤(DILI)是临床医学和药物开发的挑战。高度敏感的新型生物标志物已被鉴定用于检测扑热息痛过量后的DILI。研究目的是评估治疗剂量扑热息痛的14天试验中的生物标志物性能。PATH-BP试验是双盲的,安慰剂对照,交叉研究。个体(n=110)被随机分配接受1g扑热息痛4×每日或匹配的安慰剂2周,然后进行2周的冲洗,然后进行替代治疗。在第0天(基线)收集血液,两臂分别为4、7和14。在所有患者中测量丙氨酸转氨酶(ALT)活性。微小RNA-122(miR-122),细胞角蛋白-18(K18)和谷氨酸脱氢酶(GLDH)在对乙酰氨基酚治疗的ALT升高的患者中进行测量(从基线≥50%)。ALT在49个个体中增加(45%)。所有3种生物标志物均在ALT峰值时增加(K18扑热息痛组:18.9±9.7ng/mL,安慰剂组:11.1±5.4ng/mL,ROC-AUC=0.80,95CI0.71-0.89;miR-122:15.1±12.9fMV4.9±4.7fM,ROC-AUC=0.83,0.75-0.91;GLDH:24.6±31.1U/LV12.0±11.8U/L,ROC-AUC=0.66,0.49-0.83)。所有生物标志物均与ALT相关(K18r=0.68,miR-122r=0.67,GLDHr=0.60)。为了评估敏感性,在ALT峰值之前的访视中分析了生物标志物的表现(前3天的平均值).K18鉴定了随后的ALT增加(K18ROC-AUC=0.70,0.59-0.80;miR-122ROC-AUC=0.60,0.49-0.72,ALTROC-AUC=0.59,0.48-0.70;GLDHROC-AUC=0.70,0.50-0.90)。ALT和K18的变异性最低。总之,K18比ALT更敏感,miR-122或GLDH在试验和临床实践中对DILI的早期鉴定具有潜在的显著效用。
Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (n = 110) were randomized to receive 1 g paracetamol 4× daily or matched placebo for 2 weeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (≥50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9 ± 9.7 ng/ml, placebo arm: 11.1 ± 5.4 ng/ml, ROC-AUC = 0.80, 95% CI 0.71-0.89; miR-122: 15.1 ± 12.9fM V 4.9 ± 4.7fM, ROC-AUC = 0.83, 0.75-0.91; and GLDH: 24.6 ± 31.1U/l V 12.0 ± 11.8U/l, ROC-AUC = 0.66, 0.49-0.83). All biomarkers were correlated with ALT (K18 r = 0.68, miR-122 r = 0.67, GLDH r = 0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3 days earlier). K18 identified the subsequent ALT increase (K18 ROC-AUC = 0.70, 0.59-0.80; miR-122 ROC-AUC = 0.60, 0.49-0.72, ALT ROC-AUC = 0.59, 0.48-0.70; GLDH ROC-AUC = 0.70, 0.50-0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice.