Benesic Andreas, Jalal Kowcee, Gerbes Alexander L
Department of Medicine II, Liver Centre Munich, University Hospital, LMU Munich, Munich, Germany.
MetaHeps GmbH, Planegg, Germany.
Toxicol Sci. 2019 Oct 1;171(2):296-302. doi: 10.1093/toxsci/kfz156.
Drug-induced liver injury (DILI) is a major cause for acute liver failure and regulatory actions on novel drugs. Individual patient characteristics are the main determinant of idiosyncratic DILI, making idiosyncratic DILI (iDILI) one of the most challenging diagnoses in hepatology. Individual drug-drug interactions might play a role in iDILI. However, the current approaches to iDILI diagnosis are focused on single drugs as causative agents. For the present analysis, 48 patients with acute liver injury who took 2 drugs and who were diagnosed as iDILI were investigated. A novel in vitro test was employed using monocyte-derived hepatocyte-like cells (MH cells) generated from these patients. iDILI diagnosis and causality were evaluated using clinical causality assessment supported by Roussel-Uclaf Causality Assessment Method. In 13 of these 48 patients (27%), combinations of drugs increased toxicity in the MH test when compared with the single drugs. Interestingly, whereas in 24 cases (50%) drug-drug combinations did not enhance toxicity, in 11 cases (23%) only the combinations caused toxicity. The incidence of severe cases fulfilling Hy's law was higher in patients with positive interactions (57% vs 43%; p = .04), with acute liver failure occurring in 40% versus 8% (p = .01). The most common drug combinations causing increased toxicity were amoxicillin/clavulanate (8 of 9 cases) and diclofenac in combination with steroid hormones (4 of 9 cases). Drug-drug interactions may influence the incidence and/or the severity of idiosyncratic DILI. MH cell testing can identify relevant drug-drug interactions. The data generated by this approach may improve patient safety.
ClinicalTrials.gov NCT02353455.
药物性肝损伤（DILI）是急性肝衰竭的主要原因之一，也是新型药物监管行动的原因。个体患者特征是特异质性DILI的主要决定因素，使得特异质性DILI（iDILI）成为肝病学中最具挑战性的诊断之一。个体药物相互作用可能在iDILI中起作用。然而，目前iDILI的诊断方法主要集中在单一药物作为致病因素。在本次分析中，对48例服用两种药物且被诊断为iDILI的急性肝损伤患者进行了调查。采用一种新的体外试验，使用从这些患者中产生的单核细胞衍生的肝细胞样细胞（MH细胞）。使用由鲁塞尔 - 优克福因果关系评估方法支持的临床因果关系评估来评估iDILI诊断和因果关系。在这48例患者中的13例（27%）中，与单一药物相比，药物组合在MH试验中增加了毒性。有趣的是，虽然在24例（50%）中药物组合没有增强毒性，但在11例（23%）中只有组合导致了毒性。相互作用为阳性的患者中符合Hy法则的严重病例发生率更高（57%对43%；p = 0.04），急性肝衰竭发生率分别为40%和8%（p = 0.01）。导致毒性增加最常见的药物组合是阿莫西林/克拉维酸（9例中的8例）和双氯芬酸与甾体激素联合使用（9例中的4例）。药物相互作用可能影响特异质性DILI的发生率和/或严重程度。MH细胞检测可以识别相关的药物相互作用。这种方法产生的数据可能会提高患者安全性。
ClinicalTrials.gov NCT02353455
