Expert Review of Gastroenterology & Hepatology
ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20
Predicting idiosyncratic drug-induced liver injury – some recent advances Minjun Chen, Jürgen Borlak & Weida Tong To cite this article: Minjun Chen, Jürgen Borlak & Weida Tong (2014) Predicting idiosyncratic drug-induced liver injury – some recent advances, Expert Review of Gastroenterology & Hepatology, 8:7, 721-723, DOI: 10.1586/17474124.2014.922871 To link to this article: https://doi.org/10.1586/17474124.2014.922871
Published online: 23 May 2014.
Submit your article to this journal
Article views: 1257
View related articles
View Crossmark data
Citing articles: 9 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierh20
Editorial
Predicting idiosyncratic drug-induced liver injury – some recent advances Expert Rev. Gastroenterol. Hepatol. 8(7), 721–723 (2014)
Minjun Chen Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
Ju¨rgen Borlak‡ Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
Weida Tong‡ Author for correspondence: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA Fax: +1 870 543 7854 [email protected] ‡
Authors contributed equally
Drug-induced liver injury (DILI) is a major challenge for the pharmaceutical industry, regulatory authorities, and clinicians. It is usually categorized into ‘intrinsic’ and ‘idiosyncratic’, but DILI caused by most drugs is of an idiosyncratic nature and usually cannot be predicted from the regulatory required animal toxicity studies. Unfortunately, some individuals exposed to therapeutic dose will develop idiosyncratic DILI that might involve severe clinical outcome, and no biomarker is available to identify the susceptible patients prior to drug treatment. In this editorial, we summarized the recent advances in predicting idiosyncratic DILI and provided the perspectives to improve the prediction.
‘ Despite extensive safety testing idiosyncratic DILI remains enigmatic and cannot be predicted in preclinical and clinical trials and apart from statistical reasons other unfavorable constellations (e.g., co-medications, diverse pathophysiologies, and genetic markers) need to be considered.’ Drug-induced liver injury (DILI) is a major challenge for the pharmaceutical industry as well as the regulatory authorities and can be associated with serious clinical outcomes with recent statistics suggesting that the DILI accounts for approximately 13% of all acute liver failure cases in the USA except for those caused by acetaminophen [1]. In the past half century, DILI concerns had resulted in approximately 50 approved drugs to be withdrawn from the worldwide markets, and DILI frequently leads to regulatory actions in the USA including black box warnings and other product labeling modifications [2]. Therefore, it is an obligation of the industry and regulatory agencies to protect the public health through reliable identification of risk for DILI prior to approval for marketing. Idiosyncratic DILI – can it be predicted?
DILI is a potential complication associated with approximately 1000 drugs, albeit mostly at low frequencies. It is
usually categorized into ‘intrinsic’ and ‘idiosyncratic’; however, no conclusive evidence supports the notion that they had arisen from different mechanisms [3]. With few exceptions, that is, acetaminophen toxicity that is primarily dose dependent, DILI caused by most drugs is of an idiosyncratic or type B (=bizarre) nature. By definition, idiosyncratic DILI is not clearly dose related but host dependent and usually cannot be predicted from the regulatory required animal toxicity studies [4]. Importantly, while most patients taking therapeutic doses of culprit drugs are safe, some individuals exposed to therapeutic dose will develop idiosyncratic DILI that might involve severe clinical outcome [5]. The question remains whether individuals at risk for DILI can be identified prior to drug treatment and whether patients at risk for idiosyncratic DILI are vulnerable to all drugs or only to some specific medications? It has been discovered that some genotypes are associated with idiosyncratic DILI. For instance, carriers of the HLAB*57:01 genotype have an approximately 80-times higher risk (odd ratios = 80.6) of flucloxacillin-induced DILI that demands genetic testing [6]; nonetheless, not all carriers of this genotype will develop DILI, and the incidence of
KEYWORDS: data integration • drug safety • HLA • idiosyncratic drug-induced liver injury • predictive model
informahealthcare.com
10.1586/17474124.2014.922871
Ó 2014 Informa UK Ltd
ISSN 1747-4124
721
Editorial
Chen, Borlak & Tong
flucloxacillin–DILI is estimated to be 8.9/100,000 exposed patients. Consequently, only one carrier of the HLAB*57:01 genotype will develop liver injury at the cost of screening 500–1000 patients prior to flucloxacillin treatment [6]. The HLA association was also found in some other DILI cases but mostly with antibiotics. Intriguingly, in a recently published genome-wide association study with approximately 800 DILI patients and 200 different drugs, only very few genotypes at the genome significance threshold of odds ratio >2.0 had a clear association with DILI [7]. As a result, nongenetic biomarkers are also highly sought after, and significant progress has been made to understand the pathogenic factors that drive acute liver injury including the involvement of reactive metabolites, stress signaling, mitochondrial dysfunction and the contribution of innate immunity in liver injury. Through a better understanding of the DILI pathogenesis, some mechanistic biomarkers have been proposed such as miRNA-122, high-mobility group box-1, full length and caspase-cleaved keratin-18, and glutamate dehydrogenase to improve prediction of high-risk patients prior to severe outcomes. Recently, a panel of mechanistic biomarkers was also reported to predict the development of acetaminophen-induced liver injury in patients. Specifically, it provided earlier and more sensitive detection to acetaminophen-induced acute liver injury than alanine transaminase and other serum enzyme markers [8]. However, these biomarkers are mostly derived from the cases of acetaminophen poisoning and have not been tested for other cases of idiosyncratic DILI [8]. It is somewhat perplexing that despite the extensive safety testing in preclinical and clinical trials, idiosyncratic DILI cannot be predicted and apart from statistical reasons, other unfavorable constellations (e.g., diverse pathophysiology) need to be considered. While the current nonclinical safety testing paradigm is based on dose escalation in healhy animals for long duration, it does not accurately predict DILI in diverse patient population [9]. Although being successful in identifying toxic agents, a ‘high dosing of healthy animals’ testing strategy is not predictive for idiosyncratic DILI [10]. Indeed, a large survey revealed that conventional toxicology studies with two species (rodent and nonrodent) failed to identify the risk of DILI for approximately 45% of drug candidates as observed in subsequent clinical trials [10] and apart from risk factors, such as sex, age, race, liver disease, comorbidities and genetic factors, DILI may arise from complex comedications that potentially modulate liver injury. Furthermore, in clinical trials, the inclusion and exclusion criteria of patient enrolment are highly specific. Hence, information from such studies cannot be fully translated into the diverse patient populations that will be exposed after marketing authorization. The lack of accurate causality assessment of DILI cases is another important issue that requires consideration. There is significant underreporting of DILI cases and with the exception for some important hepatotoxic drugs, the incidence for most drugs is largely unknown [11]. Additionally, DILI can mimic all forms of acute and chronic hepatobiliary diseases. Therefore, its clinical diagnosis is largely based on exclusion of other 722
conditions rendering a definitive diagnosis of DILI challenging, while an assessment of the medical history frequently involves complex comedications as well as complementary alternative medicines and over-the-counter products. Thus, establishing a causal relationship is often difficult, and the strength and weaknesses in the causality assessment methods have been dealt with in various reviews and cases studies [12–14]. Positive outcomes of rechallenging exposures would lead to definitive answer and would be of high value for the search and identification of biomarker candidates. However, such exposures are ethically unjustified with patients being subjected to a potentially harmful condition without any therapeutic benefit. Perspectives to improve the prediction of idiosyncratic DILI
The uniqueness of idiosyncratic DILI is that it only occurs in a minority of exposed patients. To understand why only certain patients suffer from liver injury requires a comprehensive assessment of the medical history. Once pathogenic factors have been identified, these might be assessed in newly developed animal models. This so-called ‘bedside to bench’ approach can translate clinical findings into the development of predictive tools for risk evaluation. For example, proinflammatory cytokines have been reported to contribute to the development of acute DILI in patients [15] and animal treated with trovafloxacin and lipopolysaccharide, that is, a potent inducer of cytokine release recapitulated the overt events seen in the clinic at nontoxic dose [16]. Consequently, an understanding of the role of cytokines in DILI has led to the development of sophisticated co-culture in vitro systems to screen drugs with potential to cause idiosyncratic DILI [17]. There is a growing evidence to support the eminent role of immune cells in the development of idiosyncratic DILI and can be associated with fever, rash, eosinophilia and autoimmune hepatitis-like features. Thus, idiosyncratic DILI can be categorized as immune-mediated and nonimmune mediated reactions. This concept has been challenged, especially with carriers of genotypes predisposed to DILI. Some drugs that do not exhibit systemic hypersensitivity features including lapatinib, lumiracoxib and ximelagatran showed a strong association with specific HLA constellations. The search and validation of predictive biomarkers for the prevention of idiosyncratic DILI are an unmet need and an ideal biomarker will identify patients prior to drug treatment. The current serum biomarkers alanine transaminase and aspartate transaminase alert to hepatocellular damage but are not predictive for potential risks in patients [18]. In 2009, the US FDA issued a guideline for the industry to evaluate DILI in the premarketing phase, which employs a testing paradigm based on the assessment of serum aminotransferase and bilirubin (i.e., Hy’s law) [19]. DILI is a complex disease, and unfavorable chemical properties of the drug, unique susceptibility of certain individual and specific environmental factor need to be considered, thus defining the ‘multiple determinant hypothesis’ [20]. A comprehensive approach therefore requires integrating data from multiple sources encompassing chemical structure, cell-based assays, Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
Predicting idiosyncratic DILI
toxicogenomic data and clinical information [21]. The data mining and data sharing in the knowledge base will harness the advance in the development of predictive models and a mechanistic understanding of DILI, resulting in an improved DILI prediction [22]. We stress the importance of taking a concerted effort that involves multiple disciplines; cross-talk between clinicians and toxicologists to advance DILI research and management. Disclaimer
The views presented in this article do not necessarily reflect those of the US FDA.
References
Financial & competing interests disclosure
J Borlak receives funding from the German Federal Ministry for Education and Research as part of the Virtual Liver Network initiative (Grant number 031 6154). Furthermore, J Borlak is recipient of an ORISE Stipend of the US FDA which is gratefully acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
9.
Nonclinical assessment of potential hepatotoxicity in man. Available from: www.fda.gov/downloads/drugs/ scienceresearch/researchareas/ucm091453.pdf [Last accessed March 2014]
1.
Lee WM. Drug-induced acute liver failure. Clin Liver Dis 2013;17(4):575-86
2.
Chen M, Vijay V, Shi Q, et al. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today 2011;16(15-16):697-703
10.
Roth RA, Ganey PE. Intrinsic versus idiosyncratic drug-induced hepatotoxicity – two villains or one? J Pharmacol Exp Ther 2010;332(3):692-7
Olson H, Betton G, Robinson D, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000;32(1):56-67
11.
Bjornsson ES, Bergmann OM, Bjornsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013;144(7):1419-25.e1413
3.
4.
Chen M, Bisgin H, Tong L, et al. Toward predictive models for drug-induced liver injury in humans: are we there yet? Biomark Med 2014;8(2):201-13
5.
Lewis JH. Drug-induced liver injury, dosage, and drug disposition: is idiosyncrasy really unpredictable? Clin Gastroenterol Hepatol 2014. [Epub ahead of print]
6.
Daly AK, Donaldson PT, Bhatnagar P, et al. HLA-B* 5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41(7): 816-19
7.
8.
Urban TJ, Shen Y, Stolz A, et al. Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenet Genomics 2012; 22(11):784 Antoine DJ, Dear JW, Lewis PS, et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 2013;58(2):777-87
informahealthcare.com
12.
Garcia-Cortes M, Stephens C, Lucena MI, et al. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol 2011;55(3):683-91
13.
Teschke R, Frenzel C, Wolff A, et al. Drug induced liver injury: accuracy of diagnosis in published reports. Ann Hepatol 2014;13(2): 248-55
14.
Anderson N, Borlak J. Correlation versus causation? Pharmacovigilance of the analgesic flupirtine exemplifies the need for refined spontaneous ADR reporting. PLoS One 2011;6(10):e25221
15.
16.
Editorial
Steuerwald NM, Foureau DM, Norton HJ, et al. Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance. PLoS One 2013; 8(12):e81974 Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA. Lipopolysaccharide and
trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 2007;100(1):259-66 17.
Cosgrove BD, King BM, Hasan MA, et al. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol 2009;237(3):317-30
18.
Senior JR. Alanine aminotransferase: a clinical and regulatory tool for detecting liver injury-past, present, and future. Clin Pharmacol Ther 2012;92(3):332-9
19.
Guidance for industry drug-induced liver injury: premarketing clinical evaluation. Available from: www.fda.gov/downloads/ Drugs/.../Guidances/UCM174090.pdf [Last accessed March 2014]
20.
Li AP. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the “multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem Biol Interact 2002;142(1-2): 7-23
21.
Chen M, Zhang J, Wang Y, et al. Liver toxicity knowledge base (LTKB) – a systems approach to a complex endpoint. Clin Pharmacol Ther 2013;95(5):409-12
22.
Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology 2013;58(1):388-96
723
ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20
Predicting idiosyncratic drug-induced liver injury – some recent advances Minjun Chen, Jürgen Borlak & Weida Tong To cite this article: Minjun Chen, Jürgen Borlak & Weida Tong (2014) Predicting idiosyncratic drug-induced liver injury – some recent advances, Expert Review of Gastroenterology & Hepatology, 8:7, 721-723, DOI: 10.1586/17474124.2014.922871 To link to this article: https://doi.org/10.1586/17474124.2014.922871
Published online: 23 May 2014.
Submit your article to this journal
Article views: 1257
View related articles
View Crossmark data
Citing articles: 9 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierh20
Editorial
Predicting idiosyncratic drug-induced liver injury – some recent advances Expert Rev. Gastroenterol. Hepatol. 8(7), 721–723 (2014)
Minjun Chen Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
Ju¨rgen Borlak‡ Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
Weida Tong‡ Author for correspondence: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA Fax: +1 870 543 7854 [email protected] ‡
Authors contributed equally
Drug-induced liver injury (DILI) is a major challenge for the pharmaceutical industry, regulatory authorities, and clinicians. It is usually categorized into ‘intrinsic’ and ‘idiosyncratic’, but DILI caused by most drugs is of an idiosyncratic nature and usually cannot be predicted from the regulatory required animal toxicity studies. Unfortunately, some individuals exposed to therapeutic dose will develop idiosyncratic DILI that might involve severe clinical outcome, and no biomarker is available to identify the susceptible patients prior to drug treatment. In this editorial, we summarized the recent advances in predicting idiosyncratic DILI and provided the perspectives to improve the prediction.
‘ Despite extensive safety testing idiosyncratic DILI remains enigmatic and cannot be predicted in preclinical and clinical trials and apart from statistical reasons other unfavorable constellations (e.g., co-medications, diverse pathophysiologies, and genetic markers) need to be considered.’ Drug-induced liver injury (DILI) is a major challenge for the pharmaceutical industry as well as the regulatory authorities and can be associated with serious clinical outcomes with recent statistics suggesting that the DILI accounts for approximately 13% of all acute liver failure cases in the USA except for those caused by acetaminophen [1]. In the past half century, DILI concerns had resulted in approximately 50 approved drugs to be withdrawn from the worldwide markets, and DILI frequently leads to regulatory actions in the USA including black box warnings and other product labeling modifications [2]. Therefore, it is an obligation of the industry and regulatory agencies to protect the public health through reliable identification of risk for DILI prior to approval for marketing. Idiosyncratic DILI – can it be predicted?
DILI is a potential complication associated with approximately 1000 drugs, albeit mostly at low frequencies. It is
usually categorized into ‘intrinsic’ and ‘idiosyncratic’; however, no conclusive evidence supports the notion that they had arisen from different mechanisms [3]. With few exceptions, that is, acetaminophen toxicity that is primarily dose dependent, DILI caused by most drugs is of an idiosyncratic or type B (=bizarre) nature. By definition, idiosyncratic DILI is not clearly dose related but host dependent and usually cannot be predicted from the regulatory required animal toxicity studies [4]. Importantly, while most patients taking therapeutic doses of culprit drugs are safe, some individuals exposed to therapeutic dose will develop idiosyncratic DILI that might involve severe clinical outcome [5]. The question remains whether individuals at risk for DILI can be identified prior to drug treatment and whether patients at risk for idiosyncratic DILI are vulnerable to all drugs or only to some specific medications? It has been discovered that some genotypes are associated with idiosyncratic DILI. For instance, carriers of the HLAB*57:01 genotype have an approximately 80-times higher risk (odd ratios = 80.6) of flucloxacillin-induced DILI that demands genetic testing [6]; nonetheless, not all carriers of this genotype will develop DILI, and the incidence of
KEYWORDS: data integration • drug safety • HLA • idiosyncratic drug-induced liver injury • predictive model
informahealthcare.com
10.1586/17474124.2014.922871
Ó 2014 Informa UK Ltd
ISSN 1747-4124
721
Editorial
Chen, Borlak & Tong
flucloxacillin–DILI is estimated to be 8.9/100,000 exposed patients. Consequently, only one carrier of the HLAB*57:01 genotype will develop liver injury at the cost of screening 500–1000 patients prior to flucloxacillin treatment [6]. The HLA association was also found in some other DILI cases but mostly with antibiotics. Intriguingly, in a recently published genome-wide association study with approximately 800 DILI patients and 200 different drugs, only very few genotypes at the genome significance threshold of odds ratio >2.0 had a clear association with DILI [7]. As a result, nongenetic biomarkers are also highly sought after, and significant progress has been made to understand the pathogenic factors that drive acute liver injury including the involvement of reactive metabolites, stress signaling, mitochondrial dysfunction and the contribution of innate immunity in liver injury. Through a better understanding of the DILI pathogenesis, some mechanistic biomarkers have been proposed such as miRNA-122, high-mobility group box-1, full length and caspase-cleaved keratin-18, and glutamate dehydrogenase to improve prediction of high-risk patients prior to severe outcomes. Recently, a panel of mechanistic biomarkers was also reported to predict the development of acetaminophen-induced liver injury in patients. Specifically, it provided earlier and more sensitive detection to acetaminophen-induced acute liver injury than alanine transaminase and other serum enzyme markers [8]. However, these biomarkers are mostly derived from the cases of acetaminophen poisoning and have not been tested for other cases of idiosyncratic DILI [8]. It is somewhat perplexing that despite the extensive safety testing in preclinical and clinical trials, idiosyncratic DILI cannot be predicted and apart from statistical reasons, other unfavorable constellations (e.g., diverse pathophysiology) need to be considered. While the current nonclinical safety testing paradigm is based on dose escalation in healhy animals for long duration, it does not accurately predict DILI in diverse patient population [9]. Although being successful in identifying toxic agents, a ‘high dosing of healthy animals’ testing strategy is not predictive for idiosyncratic DILI [10]. Indeed, a large survey revealed that conventional toxicology studies with two species (rodent and nonrodent) failed to identify the risk of DILI for approximately 45% of drug candidates as observed in subsequent clinical trials [10] and apart from risk factors, such as sex, age, race, liver disease, comorbidities and genetic factors, DILI may arise from complex comedications that potentially modulate liver injury. Furthermore, in clinical trials, the inclusion and exclusion criteria of patient enrolment are highly specific. Hence, information from such studies cannot be fully translated into the diverse patient populations that will be exposed after marketing authorization. The lack of accurate causality assessment of DILI cases is another important issue that requires consideration. There is significant underreporting of DILI cases and with the exception for some important hepatotoxic drugs, the incidence for most drugs is largely unknown [11]. Additionally, DILI can mimic all forms of acute and chronic hepatobiliary diseases. Therefore, its clinical diagnosis is largely based on exclusion of other 722
conditions rendering a definitive diagnosis of DILI challenging, while an assessment of the medical history frequently involves complex comedications as well as complementary alternative medicines and over-the-counter products. Thus, establishing a causal relationship is often difficult, and the strength and weaknesses in the causality assessment methods have been dealt with in various reviews and cases studies [12–14]. Positive outcomes of rechallenging exposures would lead to definitive answer and would be of high value for the search and identification of biomarker candidates. However, such exposures are ethically unjustified with patients being subjected to a potentially harmful condition without any therapeutic benefit. Perspectives to improve the prediction of idiosyncratic DILI
The uniqueness of idiosyncratic DILI is that it only occurs in a minority of exposed patients. To understand why only certain patients suffer from liver injury requires a comprehensive assessment of the medical history. Once pathogenic factors have been identified, these might be assessed in newly developed animal models. This so-called ‘bedside to bench’ approach can translate clinical findings into the development of predictive tools for risk evaluation. For example, proinflammatory cytokines have been reported to contribute to the development of acute DILI in patients [15] and animal treated with trovafloxacin and lipopolysaccharide, that is, a potent inducer of cytokine release recapitulated the overt events seen in the clinic at nontoxic dose [16]. Consequently, an understanding of the role of cytokines in DILI has led to the development of sophisticated co-culture in vitro systems to screen drugs with potential to cause idiosyncratic DILI [17]. There is a growing evidence to support the eminent role of immune cells in the development of idiosyncratic DILI and can be associated with fever, rash, eosinophilia and autoimmune hepatitis-like features. Thus, idiosyncratic DILI can be categorized as immune-mediated and nonimmune mediated reactions. This concept has been challenged, especially with carriers of genotypes predisposed to DILI. Some drugs that do not exhibit systemic hypersensitivity features including lapatinib, lumiracoxib and ximelagatran showed a strong association with specific HLA constellations. The search and validation of predictive biomarkers for the prevention of idiosyncratic DILI are an unmet need and an ideal biomarker will identify patients prior to drug treatment. The current serum biomarkers alanine transaminase and aspartate transaminase alert to hepatocellular damage but are not predictive for potential risks in patients [18]. In 2009, the US FDA issued a guideline for the industry to evaluate DILI in the premarketing phase, which employs a testing paradigm based on the assessment of serum aminotransferase and bilirubin (i.e., Hy’s law) [19]. DILI is a complex disease, and unfavorable chemical properties of the drug, unique susceptibility of certain individual and specific environmental factor need to be considered, thus defining the ‘multiple determinant hypothesis’ [20]. A comprehensive approach therefore requires integrating data from multiple sources encompassing chemical structure, cell-based assays, Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
Predicting idiosyncratic DILI
toxicogenomic data and clinical information [21]. The data mining and data sharing in the knowledge base will harness the advance in the development of predictive models and a mechanistic understanding of DILI, resulting in an improved DILI prediction [22]. We stress the importance of taking a concerted effort that involves multiple disciplines; cross-talk between clinicians and toxicologists to advance DILI research and management. Disclaimer
The views presented in this article do not necessarily reflect those of the US FDA.
References
Financial & competing interests disclosure
J Borlak receives funding from the German Federal Ministry for Education and Research as part of the Virtual Liver Network initiative (Grant number 031 6154). Furthermore, J Borlak is recipient of an ORISE Stipend of the US FDA which is gratefully acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
9.
Nonclinical assessment of potential hepatotoxicity in man. Available from: www.fda.gov/downloads/drugs/ scienceresearch/researchareas/ucm091453.pdf [Last accessed March 2014]
1.
Lee WM. Drug-induced acute liver failure. Clin Liver Dis 2013;17(4):575-86
2.
Chen M, Vijay V, Shi Q, et al. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today 2011;16(15-16):697-703
10.
Roth RA, Ganey PE. Intrinsic versus idiosyncratic drug-induced hepatotoxicity – two villains or one? J Pharmacol Exp Ther 2010;332(3):692-7
Olson H, Betton G, Robinson D, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000;32(1):56-67
11.
Bjornsson ES, Bergmann OM, Bjornsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013;144(7):1419-25.e1413
3.
4.
Chen M, Bisgin H, Tong L, et al. Toward predictive models for drug-induced liver injury in humans: are we there yet? Biomark Med 2014;8(2):201-13
5.
Lewis JH. Drug-induced liver injury, dosage, and drug disposition: is idiosyncrasy really unpredictable? Clin Gastroenterol Hepatol 2014. [Epub ahead of print]
6.
Daly AK, Donaldson PT, Bhatnagar P, et al. HLA-B* 5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41(7): 816-19
7.
8.
Urban TJ, Shen Y, Stolz A, et al. Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenet Genomics 2012; 22(11):784 Antoine DJ, Dear JW, Lewis PS, et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 2013;58(2):777-87
informahealthcare.com
12.
Garcia-Cortes M, Stephens C, Lucena MI, et al. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol 2011;55(3):683-91
13.
Teschke R, Frenzel C, Wolff A, et al. Drug induced liver injury: accuracy of diagnosis in published reports. Ann Hepatol 2014;13(2): 248-55
14.
Anderson N, Borlak J. Correlation versus causation? Pharmacovigilance of the analgesic flupirtine exemplifies the need for refined spontaneous ADR reporting. PLoS One 2011;6(10):e25221
15.
16.
Editorial
Steuerwald NM, Foureau DM, Norton HJ, et al. Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance. PLoS One 2013; 8(12):e81974 Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA. Lipopolysaccharide and
trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 2007;100(1):259-66 17.
Cosgrove BD, King BM, Hasan MA, et al. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol 2009;237(3):317-30
18.
Senior JR. Alanine aminotransferase: a clinical and regulatory tool for detecting liver injury-past, present, and future. Clin Pharmacol Ther 2012;92(3):332-9
19.
Guidance for industry drug-induced liver injury: premarketing clinical evaluation. Available from: www.fda.gov/downloads/ Drugs/.../Guidances/UCM174090.pdf [Last accessed March 2014]
20.
Li AP. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the “multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem Biol Interact 2002;142(1-2): 7-23
21.
Chen M, Zhang J, Wang Y, et al. Liver toxicity knowledge base (LTKB) – a systems approach to a complex endpoint. Clin Pharmacol Ther 2013;95(5):409-12
22.
Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology 2013;58(1):388-96
723
