用nR改良海氏法则及PALT评估药物性肝损伤研究进展.pdf
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1、中国药物警戒 第 21 卷第 1 期 2024 年 1 月 January,2024,Vol.21,No.1117DOI:10.19803/j.1672-8629.20230615 中图分类号:R969;R994.11文献标志码:A 文章编号:1672-8629(2024)01-0117-04作者简介:詹姆斯布坎南(JAMES Buchanan),博士,药品安全及临床毒理。E-mail:JHepatotoxicity associated with drugs,herbal medications and supplements continues to represent a signifi
2、cant public health concern globally.In the United States(US),liver injury due to drugs has been the single most frequent cause of safety-related marketing authorization withdrawals by the US Food and Drug Administration(FDA)1.Although it is often assumed that most cases of liver injury are due to me
3、dications,it has been increasingly appreciated that herbal medications and supplements are also a common source of liver injury.The US Acute Liver Failure Study Group(ALFSG)reported that among 253 patients with drug-induced acute liver injury or liver failure,16.3%of cases were associated with compl
4、ementary or alternative therapies of which herbal supplements accounted for 63.4%2.A review of 31 drug-induced liver injury(DILI)cases in Singapore reported that complementary and alternative medicines were implicated in 55%of cases 3.A retrospective study in China found that of 25 927 confirmed DIL
5、I cases 26.81%were associated with the use of traditional Chinese medicines or herbal and dietary supplements 4.Three mechanisms are principally responsible for intrinsic DILI:mitochondrial dysfunction,oxidative stress,and disruption in bile acid homeostasis 5.These are not necessarily independent p
6、rocesses but rather may be involved together.Genetic variation,drug and Assessment of drug-induced liver injury via nR modified Hys law and PALTBUCHANAN James(Covilance LLC,Belmont,CA,USA)Abstract:Hepatotoxicity associated with drugs,herbal medications and other complementary or alternative therapie
7、s has been a global concern for safety professionals and regulatory authorities.Instant identification of liver injury remains a challenge during both clinical development and in the post-marketing period.Advances have been made in the criteria used to identify cases of hepatotoxicity that are most
8、likely to progress to liver failure or death.In addition,new methods are available to estimate the magnitude of hepatocyte loss associated with liver injury.This paper reviews these new methodologies and their applications to the ongoing monitoring and evaluation of product-related hepatoxicity.Keyw
9、ords:drug-induced liver injury(DILI);herbal medications;complementary therapies;alternative therapies;Hys Law;eDISH;R value;nR value;PALT用 nR 改良海氏法则及 PALT 评估药物性肝损伤研究进展詹姆斯布坎南(Covilance LLC,美国加利福尼亚州贝尔蒙特市)摘要:与药物、草药和其他补充或替代疗法相关的肝毒性一直是全球安全专业人员和监管机构关注的问题。在临床开发和上市后阶段及时识别肝损伤仍是一项挑战。目前,用于识别最有可能发展为肝衰竭或死亡的肝毒性病例
10、标准已经取得最新进展,并建立了可用于评估与肝损伤相关肝细胞损失程度的新方法。本文将对这些新方法及其在相关肝毒性持续监测和评估中的应用进行回顾。关键词:药物性肝损伤(DILI);草药;补充疗法;替代疗法;海氏法则;药物引起严重肝毒性的四象限评价图表;R 值;nR 值;谷丙转氨酶的 P 值environmental factors may determine susceptibility to idiosyncratic DILI,that is hepatic injury that is less predictable than intrinsic DILI 6.The mechanisms
11、 that lead to DILI appear to be similar across drugs,herbal medications and dietary supplements which allows for a common framework that can be applied to identify cases of DILI across these various compounds.The method by which DILI may be detected was advanced greatly by the observation of Dr.ZIMM
12、ERMAN 7 that“drug-induced hepatocellular jaundice is a serious lesion,”with mortality ranging from 10%to 50%.The concept of hepatocellular injury accompanied by hyperbilirubinemia was subsequently refined by the FDA as an evaluation of biomarkers,specifically alanine aminotransferase(ALT),aspartate
13、aminotransferase(AST)and total bilirubin.Circumstances in which elevations in aminotransferases 3 times the upper limit of normal(UNL)accompanied by elevations in total bilirubin of 2x ULN embodied the concept of“Hys Law”and became adopted as a means to identify instances indicative of the potential
14、 for DILI.The predictive value of Hys Law has been subsequently validated by BJORNSSON&OLSSON 8 and ANDRADE et al.9.Dr.GUO and SENIOR,both at FDA,were the first to develop a graphical tool to screen laboratory datasets for elevations of transaminases and bilirubin that met the definition of possible
15、 Hys Law cases.The application was called eDISH for“evaluation of drug-induced serious hepatotoxicity”10.This approach 国际研究进展中国药物警戒 第 21 卷第 1 期 2024 年 1 月 January,2024,Vol.21,No.1118to the graphical display of hepatic laboratory data has subsequently been adopted by safety specialists in industry,re
16、gulatory authorities and academia.The American Statistical Associations Biopharmaceutical Working Group taskforce on Interactive Safety Graphics has developed an open-source interactive graphical tool based on the eDISH display 11.While DILI can be of a hepatocellular,cholestatic or mixed type,the f
17、ocus typically is on cases involving hepatocellular damage as this is the principal type of drug-induced liver injury of concern.Although drugs may also cause cholestatic damage,they generally do not cause the degree of morbidity and mortality associated with hepatocellular damage.To this point,the
18、FDA guidance for DILI evaluation 1 stated that“cholestatic injuries are less likely to lead to death or transplant”and expanded the definition of a possible Hys Law case to exclude those with a prominent cholestatic component.Initially,hepatocellular processes were separated from cholestatic ones by
19、 evaluating the extent of elevation in alkaline phosphatase.If the alkaline phosphatase level was less than 2x ULN,a cholestatic process could be reasonably excluded 12.Subsequently,it came to be appreciated that instances of hepatocellular DILI may occur when the alkaline phosphatase(ALP)is elevate
20、d to some degree above 2x ULN.Instead of relying on the absolute value of alkaline phosphatase,the magnitude of change in alkaline phosphatase relative to the change in ALT was proposed by the Council for International Organizations of Medical Sciences 9 and became the preferred method to separate h
21、epatocellular from cholestatic processes 13-14.This ratio,referred to as the R value,is calculated as(ALT ULN for ALT)(ALP ULN for ALP).An R value 5 represents a primarily hepatocellular process,a value 2 indicates a principally cholestatic process and intermediate values denote a mixed hepatocellul
22、ar/cholestatic process.Thus,focusing attention on possible Hys Law cases in which the R value is 5 would have better sensitivity to identify possible DILI injury of a hepatocellular nature than reliance on the absolute alkaline phosphatase value.The members of the Spanish DILI Registry 15 sought to
23、improve the method by which true Hys Law cases could be identified,that is DILI cases that progressed to acute liver failure.They investigated the utility of the R value as well as a modified version called the nR(for new R)value.The nR value is calculated twice once using ALT and a second time usin
24、g AST.The AST calculation is similar to that for ALT with the substitution of the AST value and its ULN:(AST AST ULN)(ALP ALP ULN).The calculation using ALT is compared to that using AST and the greater value becomes the nR value.The utility of using R and nR values was compared to the traditional e
25、DISH thresholds of ALT 3x ULN and total bilirubin 2x ULN to detect DILI cases that progressed to acute liver failure.Similar to the injury definitions described above,the investigators considered a case to be hepatocellular when R or nR was 5 or greater,cholestatic when R or nR was 2 or less,and mix
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- nR 改良 法则 PALT 评估 药物性 损伤 研究进展
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