R Value-Based Criteria Outperform Alkaline Phosphatase Less than Twice Normal in Identifying Hy's Law Cases in Clinical Trials.

IF 3.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Safety Pub Date : 2025-08-31 DOI:10.1007/s40264-025-01603-z

Jasmine Amirzadegan, Edwige Chiogo Vouffo, Ling Lan, Eileen Navarro Almario, Mark I Avigan, Paul H Hayashi

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引用次数: 0

Abstract

Background: It is unknown whether nR value [(ALT or AST/ULN) ÷ (AP/ULN)] ≥ 5 is better than alkaline phosphatase less than twice the upper limit of normal (AP < 2x ULN) in identifying hepatocellular drug-induced liver injury (HC DILI) consistent with Hy's law in clinical trials.

Objective: We aimed to compare nR value ≥ 5 and AP < 2x ULN in clinical trial DILI cases with ALT or AST ≥ 3x ULN and total bilirubin (TB) > 2x ULN.

Methods: We retrospectively categorized clinical trial, DILI cases from July 2020 to April 2024 with ALT or AST ≥ 3x ULN and jaundice as meeting nR value ≥ 5, AP < 2x ULN, both, or neither. We determined positive predictive values (PPVs) and sensitivities for HC DILI-related fatality (death or liver transplant) and acute liver failure (ALF).

Results: Of 1314 liver injuries across 73 drug applications, 294 (22%) were attributed to DILI; 55 had ALT or AST ≥ 3x ULN and TB > 2x ULN. We excluded three cases (Gilbert's, high baseline enzymes, hepatitis B reactivation). Of 52 remaining, 16 (31%) met nR ≥ 5, five (10%) AP < 2x ULN, 21 (40%) both, and 10 (19%) neither. There were four DILI fatalities. Excluding one cholestatic fatality, nR ≥ 5 and AP < 2x ULN had PPVs for HC DILI fatality of 8 and 4%, respectively; sensitivities were 100 and 33%, respectively. One patient survived HC DILI-related ALF. Including this ALF case with the fatalities, nR ≥ 5 and AP < 2x ULN had PPVs of 11 and 4%, respectively; sensitivities were 100 and 25%, respectively. All fatalities and ALF cases were due to different drugs.

Conclusion: While the number of cases with the most severe DILI outcomes was small, particularly those that resulted in fatalities or ALF, nR ≥ 5 better approximated Hy's Law and was more sensitive than AP < 2x ULN in detecting fatalities and ALF.

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在临床试验中，基于R值的标准在识别Hy氏症病例方面优于碱性磷酸酶低于正常水平的两倍。

背景：尚不清楚nR值[（ALT或AST/ULN） ÷ （AP/ULN）]≥5是否优于碱性磷酸酶低于正常上限（AP）的两倍。目的：比较nR值≥5与AP 2x ULN。方法：回顾性分类临床试验，2020年7月至2024年4月期间ALT或AST≥3x ULN且黄疸符合nR值≥5的DILI病例，AP结果：在73个药物应用的1314例肝损伤中，294例（22%）归因于DILI；55例ALT或AST≥3倍ULN， TB≥10倍ULN。我们排除了三例病例（吉尔伯特氏病、高基线酶、乙型肝炎再激活）。在剩下的52例中，16例（31%）符合nR≥5,5例（10%）符合AP。结论：虽然DILI结果最严重的病例数量较少，特别是导致死亡或ALF的病例，但nR≥5更接近Hy定律，并且比AP更敏感

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Safety 医学-毒理学

CiteScore

7.60

自引率

7.10%

发文量

112

审稿时长

6-12 weeks

期刊介绍： Drug Safety is the official journal of the International Society of Pharmacovigilance. The journal includes: Overviews of contentious or emerging issues. Comprehensive narrative reviews that provide an authoritative source of information on epidemiology, clinical features, prevention and management of adverse effects of individual drugs and drug classes. In-depth benefit-risk assessment of adverse effect and efficacy data for a drug in a defined therapeutic area. Systematic reviews (with or without meta-analyses) that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. Original research articles reporting the results of well-designed studies in disciplines such as pharmacoepidemiology, pharmacovigilance, pharmacology and toxicology, and pharmacogenomics. Editorials and commentaries on topical issues. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Drug Safety Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.