TY - JOUR
T1 - Current challenges and controversies in drug-induced liver injury
AU - Corsini, Alberto
AU - Ganey, Patricia
AU - Ju, Cynthia
AU - Kaplowitz, Neil
AU - Pessayre, Dominique
AU - Roth, Robert
AU - Watkins, Paul B.
AU - Albassam, Mudher
AU - Liu, Baolian
AU - Stancic, Saray
AU - Suter, Laura
AU - Bortolini, Michele
PY - 2012
Y1 - 2012
N2 - Current key challenges and controversies encountered in the identification of potentially hepatotoxic drugs and the assessment of drug-induced liver injury (DILI) are covered in this article.There is substantial debate over the classification of DILI itself, including the definition and validity of terms such as 'intrinsic' and 'idiosyncratic'. So-called idiosyncratic DILI is typically rare and requires one or more susceptibility factors in individuals. Consequently, it has been difficult to reproduce in animal models, which has limited the understanding of its underlying mechanisms despite numerous hypotheses. Advances in predictive models would also help to enable preclinical elimination of drug candidates and development of novel biomarkers.A small number of liver laboratory tests have been routinely used to help identify DILI, but their interpretation can be limited and confounded by multiple factors. Improved preclinical and clinical biomarkers are therefore needed to accurately detect early signals of liver injury, distinguish drug hepatotoxicity from other forms of liver injury, and differentiate mild from clinically important liver injury. A range of potentially useful biomarkers are emerging, although so far most have only been used preclinically, with only a few validated and used in the clinic for specific circumstances. Advances in the development of genomic biomarkers will improve the prediction and detection of hepatic injury in future.Establishing a definitive clinical diagnosis of DILI can be difficult, since it is based on circumstantial evidence by excluding other aetiologies and, when possible, identifying a drug-specific signature. DILI signals based on standard liver test abnormalities may be affected by underlying diseases such as hepatitis B and C, HIV and cancer, as well as the concomitant use of hepatotoxic drugs to treat some of these conditions. Therefore, a modified approach to DILI assessment is justified in these special populations and a suggested framework is presented that takes into account underlying disease when evaluating DILI signals in individuals.Detection of idiosyncratic DILI should, in some respects, be easier in the postmarketing setting compared with the clinical development programme, since there is a much larger and more varied patient population exposure over longer timeframes. However, postmarketing safety surveillance is currently limited by the quantity and quality of information available to make an accurate diagnosis, the lack of a control group and the rarity of cases. The pooling of multiple healthcare databases, which could potentially contain different types of patient data, is advised to address some of these deficiencies.
AB - Current key challenges and controversies encountered in the identification of potentially hepatotoxic drugs and the assessment of drug-induced liver injury (DILI) are covered in this article.There is substantial debate over the classification of DILI itself, including the definition and validity of terms such as 'intrinsic' and 'idiosyncratic'. So-called idiosyncratic DILI is typically rare and requires one or more susceptibility factors in individuals. Consequently, it has been difficult to reproduce in animal models, which has limited the understanding of its underlying mechanisms despite numerous hypotheses. Advances in predictive models would also help to enable preclinical elimination of drug candidates and development of novel biomarkers.A small number of liver laboratory tests have been routinely used to help identify DILI, but their interpretation can be limited and confounded by multiple factors. Improved preclinical and clinical biomarkers are therefore needed to accurately detect early signals of liver injury, distinguish drug hepatotoxicity from other forms of liver injury, and differentiate mild from clinically important liver injury. A range of potentially useful biomarkers are emerging, although so far most have only been used preclinically, with only a few validated and used in the clinic for specific circumstances. Advances in the development of genomic biomarkers will improve the prediction and detection of hepatic injury in future.Establishing a definitive clinical diagnosis of DILI can be difficult, since it is based on circumstantial evidence by excluding other aetiologies and, when possible, identifying a drug-specific signature. DILI signals based on standard liver test abnormalities may be affected by underlying diseases such as hepatitis B and C, HIV and cancer, as well as the concomitant use of hepatotoxic drugs to treat some of these conditions. Therefore, a modified approach to DILI assessment is justified in these special populations and a suggested framework is presented that takes into account underlying disease when evaluating DILI signals in individuals.Detection of idiosyncratic DILI should, in some respects, be easier in the postmarketing setting compared with the clinical development programme, since there is a much larger and more varied patient population exposure over longer timeframes. However, postmarketing safety surveillance is currently limited by the quantity and quality of information available to make an accurate diagnosis, the lack of a control group and the rarity of cases. The pooling of multiple healthcare databases, which could potentially contain different types of patient data, is advised to address some of these deficiencies.
KW - Biomarkers
KW - Liver-disorders
KW - Liver-injury
KW - Postmarketing-surveillance
UR - http://www.scopus.com/inward/record.url?scp=84868618214&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868618214&partnerID=8YFLogxK
U2 - 10.2165/11632970-000000000-00000
DO - 10.2165/11632970-000000000-00000
M3 - Article
C2 - 23137150
AN - SCOPUS:84868618214
VL - 35
SP - 1099
EP - 1117
JO - Drug Safety
JF - Drug Safety
SN - 0114-5916
IS - 12
ER -