Jasmine Amirzadegan, Edwige Chiogo Vouffo, Ling Lan, Eileen Navarro Almario, Mark I Avigan, Paul H Hayashi
{"title":"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。","authors":"Jasmine Amirzadegan, Edwige Chiogo Vouffo, Ling Lan, Eileen Navarro Almario, Mark I Avigan, Paul H Hayashi","doi":"10.1007/s40264-025-01603-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"R Value-Based Criteria Outperform Alkaline Phosphatase Less than Twice Normal in Identifying Hy's Law Cases in Clinical Trials.\",\"authors\":\"Jasmine Amirzadegan, Edwige Chiogo Vouffo, Ling Lan, Eileen Navarro Almario, Mark I Avigan, Paul H Hayashi\",\"doi\":\"10.1007/s40264-025-01603-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":11382,\"journal\":{\"name\":\"Drug Safety\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-08-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Safety\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40264-025-01603-z\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Safety","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40264-025-01603-z","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
R Value-Based Criteria Outperform Alkaline Phosphatase Less than Twice Normal in Identifying Hy's Law Cases in Clinical Trials.
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.
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.
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Original research articles reporting the results of well-designed studies in disciplines such as pharmacoepidemiology, pharmacovigilance, pharmacology and toxicology, and pharmacogenomics.
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