‘Hy's law,’ the ‘Rezulin Rule,’ and other predictors of severe drug‐induced hepatotoxicity: putting risk‐benefit into perspective

Lewis, James H.

doi:10.1002/pds.1209

Cited by 79 publications

(35 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…50 Indeed, the late Hyman Zimmerman found little, if any, support in the literature or in his experience for avoiding the use of most potentially hepatotoxic medications in patients with liver disease. 33,51,52 Although exceptions do exist (such as the increased risk of hepatotoxicity developing in patients with a fatty liver receiving methotrexate or the use of highly active antiretroviral therapy or antituberculosis medications in patients with viral hepatitis B or C), 33 statins do not appear to share that susceptibility. Indeed, pravastatin has been used safely in the management of hypercholesterolemia in liver transplant recipients 28,32,53 and in patients with PBC 29,30 and as a potential treatment option for NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial

et al. 2007

Self Cite

View full text Add to dashboard Cite

The hepatotoxic potential of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in patients with underlying chronic liver disease remains controversial. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that compared pravastatin (80 mg) to a placebo administered once daily to hypercholesterolemic subjects greater than 18 years of age with at least a 6-month history of compensated chronic liver disease and with a low-density lipoprotein cholesterol (LDL-C) level greater than or equal to 100 mg/dL and a triglyceride (TG) level lower than 400 mg/dL. The efficacy was determined by the percentage change in LDL-C [along with the total cholesterol (TC), high-density lipoprotein cholesterol, and TG] from the baseline to week 12. The safety was analyzed by the proportion of subjects who developed at least 1 alanine aminotransferase (ALT) value greater than or equal to 2 times the upper limit of normal for those with normal ALT at the baseline or a doubling of the baseline ALT for those with elevated ALT at the baseline during 36 weeks of treatment. A total of 630 subjects were screened, and 326 subjects were randomized; nonalcoholic fatty liver disease was present in 64%, and chronic hepatitis C was present in 23%. In the intent-to-treat population, pravastatin (80 mg/day) significantly lowered the mean LDL-C, TC, and TG values at week 12 and at other times (weeks 4, 8, 24, and 36) in comparison with the placebo. The incidence of subjects who met the primary prespecified ALT event definition was lower in the pravastatin group at all times over the 36 weeks of therapy in comparison with the placebo group, although the difference was not statistically significant. No differences were seen on the basis of the baseline ALT values or among the different liver disease groups. Conclusion: High-dose pravastatin (80 mg/day) administered to hypercholesterolemic subjects with chronic liver disease significantly lowered LDL-C, TC, and TGs in comparison with the placebo and was safe and well tolerated. The concern over an increased potential for statin-induced hepatotoxicity in patients with chronic liver disease appears to be lessened on the basis of these results.

show abstract

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…This clinical guideline states that patients with an increase in transaminases (>3Â upper limit of normal [ULN]) in combination with an increase in serum total bilirubin (>2Â ULN) are especially at risk of developing drug-induced hepatotoxicity if no underlying causes are present. 25,31,34,37 In this regard, having additional mechanistically distinct biomarkers could help increase confidence in assessing risk. In the preclinical setting with laboratory animals that are inbred or purebred, it can be extremely difficult to clearly identify an early signal for hepatotoxicity that might translate clinically.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies

et al. 2015

View full text Add to dashboard Cite

MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases.

show abstract

“…Nine of the 37 patients died, but in most cases the deaths were not clearly hepatotoxicity-related. Only one autopsy was done and it showed a small, friable and diffusely mottled liver suggestive of severe diffuse hepatic necrosis, but liver failure from ximelagatran might have contributed to some of the other deaths (He 2004;Lewis 2006;Kaplowitz 2006;Senior 2006;Temple 2006). Because severe hepatotoxicity was observed in an orthopedic surgery trial in an extended treatment of 35 days, Exanta was withdrawn in February 2006 from the 22 countries in which it had been approved, and further development in the United States was abandoned.…”

Section: Exanta (Ximelagatran)mentioning

confidence: 99%

ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury

Chalasani

Hayashi

Bonkovsky

et al. 2014

American Journal of Gastroenterology

680

656

View full text Add to dashboard Cite

‘Hy's law,’ the ‘Rezulin Rule,’ and other predictors of severe drug‐induced hepatotoxicity: putting risk‐benefit into perspective

Cited by 79 publications

References 79 publications

Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial

Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial

Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies

ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury

Contact Info

Product

Resources

About