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Tesfaldet B, Patel T, Chen M, Pucino F, Rosario L, Hayashi P, Navarro Almario E. Composite Plot for Visualizing Aminotransferase and Bilirubin Changes in Clinical Trials of Subjects with Abnormal Baseline Values. Drug Saf 2024; 47:699-710. [PMID: 38642292 PMCID: PMC11182847 DOI: 10.1007/s40264-024-01425-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2024] [Indexed: 04/22/2024]
Abstract
INTRODUCTION On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. OBJECTIVE The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. METHODS The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. RESULTS The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. CONCLUSION For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values.
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Affiliation(s)
- Bereket Tesfaldet
- U.S. FDA, Center for Food Safety and Nutrition, Office of Analytics and Outreach, College Park, MD, USA.
- , Wiley Building, 5001 Campus Drive, College Park, MD, 20740, USA.
| | - Tejas Patel
- U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs, Silver Spring, MD, USA
| | - Minjun Chen
- U.S. FDA, Office of the Chief Scientist, National Center for Toxicology Research, Division of Bioinformatics and Biostatistics, Jefferson, AR, USA
| | - Frank Pucino
- U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs, Silver Spring, MD, USA
| | - Lilliam Rosario
- U.S. FDA, Center for Drug Evaluation and Research, Office of Translational Sciences, Office of Computational Science, Silver Spring, MD, USA
| | - Paul Hayashi
- U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs, Silver Spring, MD, USA
| | - Eileen Navarro Almario
- U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs, Silver Spring, MD, USA
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Merz M, Fettiplace A, Marcinak J, Tillmann HL, Rockey DC, Kullak-Ublick GA. Liver toxicity in oncology trials and beyond: a simplified concept for management of hepatocellular drug-induced liver injury in patients with abnormal baseline liver tests. Expert Opin Drug Saf 2024; 23:527-537. [PMID: 38482670 DOI: 10.1080/14740338.2024.2327509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 01/26/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on levels of liver test changes that should trigger action, such as drug interruption or discontinuation. METHODS We provide an innovative approach to manage hepatocellular DILI in oncology trials for patients with abnormal baseline alanine aminotransferase (ALT) levels. The algorithm proposed is based on mathematical derivation of action thresholds from those generally accepted for patients with normal baselines. RESULTS The resulting algorithm is grouped by level of baseline abnormality and avoids calculation of baseline multiples. Suggested layered action levels are 4, 6, and 11 × Upper Limit of Normal (ULN) for patients with baseline ALT between 1.5 and 3 × ULN, and 6, 8, and 12 × ULN for patients with baseline ALT between 3 and 5 × ULN, respectively. CONCLUSIONS Our concept and resulting algorithm are consistent, transparent, and easy to follow, and the method for derivation from consensus-based thresholds may also be applicable to other drug toxicity areas.
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Affiliation(s)
- Michael Merz
- Michael Merz Consulting, Freiburg, Germany
- Mechanistic Safety, Patient Safety and Pharmacovigilance, Global Drug Development, Novartis, Basel, Switzerland
| | | | - John Marcinak
- Medical Safety Evaluation, Pharmacovigilance and Patient Safety, AbbVie, North Chicago, IL, USA
| | - Hans L Tillmann
- Division Gastroenterology, Hepatology & Nutrition, Department of Medicine, East Carolina University, Greenville, NC, USA
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, Charleston, SC, USA
| | - Gerd A Kullak-Ublick
- Mechanistic Safety, Patient Safety and Pharmacovigilance, Global Drug Development, Novartis, Basel, Switzerland
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Marquez L, Raheja R, Chan-Liston M, Marcinak J, Estilo A, Pineda Salgado L, Jiang J, Chang C, Beninger P. Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use. Drug Saf 2024; 47:1-22. [PMID: 37874451 DOI: 10.1007/s40264-023-01360-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2023] [Indexed: 10/25/2023]
Abstract
The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.
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Affiliation(s)
- Loreta Marquez
- Janssen Research and Development, LLC, Raritan, NJ, USA.
| | | | | | | | - Alvin Estilo
- Otsuka Pharmaceutical Development, Inc. (OPDC), Princeton, NJ, USA
| | | | - Jason Jiang
- Daiichi Sankyo, Inc., Basking Ridge, NJ, USA
| | | | - Paul Beninger
- Public Health and Community Medicine, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA
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Salama II, Sami SM, Salama SI, Abdel-Latif GA, Shaaban FA, Fouad WA, Abdelmohsen AM, Raslan HM. Current and novel modalities for management of chronic hepatitis B infection. World J Hepatol 2023; 15:585-608. [PMID: 37305370 PMCID: PMC10251278 DOI: 10.4254/wjh.v15.i5.585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/13/2023] [Accepted: 04/12/2023] [Indexed: 05/24/2023] Open
Abstract
Over 296 million people are estimated to have chronic hepatitis B viral infection (CHB), and it poses unique challenges for elimination. CHB is the result of hepatitis B virus (HBV)-specific immune tolerance and the presence of covalently closed circular DNA as mini chromosome inside the nucleus and the integrated HBV. Serum hepatitis B core-related antigen is the best surrogate marker for intrahepatic covalently closed circular DNA. Functional HBV "cure" is the durable loss of hepatitis B surface antigen (HBsAg), with or without HBsAg seroconversion and undetectable serum HBV DNA after completing a course of treatment. The currently approved therapies are nucleos(t)ide analogues, interferon-alpha, and pegylated-interferon. With these therapies, functional cure can be achieved in < 10% of CHB patients. Any variation to HBV or the host immune system that disrupts the interaction between them can lead to reactivation of HBV. Novel therapies may allow efficient control of CHB. They include direct acting antivirals and immunomodulators. Reduction of the viral antigen load is a crucial factor for success of immune-based therapies. Immunomodulatory therapy may lead to modulation of the host immune system. It may enhance/restore innate immunity against HBV (as toll-like-receptors and cytosolic retinoic acid inducible gene I agonist). Others may induce adaptive immunity as checkpoint inhibitors, therapeutic HBV vaccines including protein (HBsAg/preS and hepatitis B core antigen), monoclonal or bispecific antibodies and genetically engineered T cells to generate chimeric antigen receptor-T or T-cell receptor-T cells and HBV-specific T cells to restore T cell function to efficiently clear HBV. Combined therapy may successfully overcome immune tolerance and lead to HBV control and cure. Immunotherapeutic approaches carry the risk of overshooting immune responses causing uncontrolled liver damage. The safety of any new curative therapies should be measured in relation to the excellent safety of currently approved nucleos(t)ide analogues. Development of novel antiviral and immune modulatory therapies should be associated with new diagnostic assays used to evaluate the effectiveness or to predict response.
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Affiliation(s)
- Iman Ibrahim Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt.
| | - Samia M Sami
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Somaia I Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Ghada A Abdel-Latif
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Fatma A Shaaban
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Walaa A Fouad
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Aida M Abdelmohsen
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Hala M Raslan
- Department of Internal Medicine, National Research Centre, Giza 12411, Dokki, Egypt
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Lewis JH, Khaldoyanidi SK, Britten CD, Wei AH, Subklewe M. Clinical Significance of Transient Asymptomatic Elevations in Aminotransferase (TAEAT) in Oncology. Am J Clin Oncol 2022; 45:352-365. [PMID: 35848749 PMCID: PMC9311471 DOI: 10.1097/coc.0000000000000932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Monitoring for liver injury remains an important aspect of drug safety assessment, including for oncotherapeutics. When present, drug-induced liver injury may limit the use or result in the discontinuation of these agents. Drug-induced liver injury can exhibit with a wide spectrum of clinical and biochemical manifestations, ranging from transient asymptomatic elevations in aminotransferases (TAEAT) to acute liver failure. Numerous oncotherapeutics have been associated with TAEAT, with published reports indicating a phenomenon in which patients may be asymptomatic without overt liver injury despite the presence of grade ≥3 aminotransferase elevations. In this review, we discuss the occurrence of TAEAT in the context of oncology clinical trials and clinical practice, as well as the clinical relevance of this phenomenon as an adverse event in response to oncotherapeutics and the related cellular and molecular mechanisms that may underlie its occurrence. We also identify several gaps in knowledge relevant to the diagnosis and the management of TAEAT in patients receiving oncotherapeutics, and identify areas warranting further study to enable the future development of consensus guidelines to support clinical decision-making.
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Affiliation(s)
| | | | | | - Andrew H. Wei
- The Alfred Hospital and Monash University, Melbourne, Victoria, Australia
| | - Marion Subklewe
- University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
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Hepatotoxicity of iodine-131 ablation for post-surgical differentiated thyroid cancer patients with hepatitis B virus infection. Clin Res Hepatol Gastroenterol 2021; 45:101631. [PMID: 33662775 DOI: 10.1016/j.clinre.2021.101631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/20/2020] [Accepted: 01/13/2021] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Radioiodine (Iodine-131, 131I) ablation is a standard treatment for differentiated thyroid cancer (DTC) after thyroidectomy. Hepatotoxicity is a rare side effect of 131I, and little information is available on the hepatotoxicity of 131I ablation for post-surgical DTC patients with hepatitis B virus (HBV) infection. METHODS We performed a retrospective study of 94 post-surgical DTC patients between November 2012 and August 2015 in our hospital. All the patients had been screened for HBV infection and divided into HBV group and non-HBV group. Clinical data were compared between the two groups. RESULTS 14 patients with HBV infection and 80 patients without HBV infection were analyzed. The baseline characteristics of the two groups had no statistical differences. Incidence of hepatotoxicity was higher in HBV group than in non-HBV group and HBV infection was confirmed as a risk factor of hepatotoxicity by univariate and multivariate regression analysis. CONCLUSION Post-surgical DTC patients with HBV infection were prone to hepatotoxicity by 131I ablation treatment. Physicians should pay more attention to the liver function of patients at risk.
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Teschke R, Danan G. The LiverTox Paradox-Gaps between Promised Data and Reality Check. Diagnostics (Basel) 2021; 11:diagnostics11101754. [PMID: 34679453 PMCID: PMC8534640 DOI: 10.3390/diagnostics11101754] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/16/2022] Open
Abstract
The LiverTox database compiles cases of idiosyncratic drug-induced liver injury (iDILI) with the promised aims to help identify hepatotoxicants and provide evidence-based information on iDILI. Weaknesses of this approach include case selection merely based on published case number and not on a strong causality assessment method such as the Roussel Uclaf Causality Assessment Method (RUCAM). The aim of this analysis was to find out whether the promised aims have been achieved by comparison of current iDILI case data with those promised in 2012 in LiverTox. First, the LiverTox criteria of likelihood categories applied to iDILI cases were analyzed regarding robustness. Second, the quality was analyzed in LiverTox cases caused by 46 selected drugs implicated in iDILI. LiverTox included iDILI cases of insufficient quality because most promised details were not fulfilled: (1) Standard liver injury definition; (2) incomplete narratives or inaccurate for alternative causes; and (3) not a single case was assessed for causality with RUCAM, as promised. Instead, causality was arbitrarily judged on the iDILI case number presented in published reports with the same drug. All of these issues characterize the paradox of LiverTox, requiring changes in the method to improve data quality and database reliability. In conclusion, establishing LiverTox is recognized as a valuable effort, but the paradox due to weaknesses between promised data quality and actual data must be settled by substantial improvements, including, for instance, clear definition and identification of iDILI cases after evaluation with RUCAM to establish a robust causality grading.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-60590 Frankfurt/Main, Germany
- Correspondence:
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France;
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Treem WR, Palmer M, Lonjon-Domanec I, Seekins D, Dimick-Santos L, Avigan MI, Marcinak JF, Dash A, Regev A, Maller E, Patwardhan M, Lewis JH, Rockey DC, Di Bisceglie AM, Freston JW, Andrade RJ, Chalasani N. Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis. Drug Saf 2021; 44:133-165. [PMID: 33141341 PMCID: PMC7847464 DOI: 10.1007/s40264-020-01014-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.
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Affiliation(s)
| | - Melissa Palmer
- Takeda, Cambridge, MA, USA
- Liver Consulting LLC, New York, NY, USA
| | | | | | | | - Mark I Avigan
- US Food and Drug Administration, Silver Spring, MD, USA
| | | | - Ajit Dash
- , Genentech, South San Francisco, CA, USA
| | - Arie Regev
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Eric Maller
- Pfizer, Collegeville, PA, USA
- MEMS Biopharma Consulting, LLC, Wynnewood, PA, USA
| | | | | | - Don C Rockey
- Medical University of South Carolina, Charleston, SC, USA
| | | | - James W Freston
- University of Connecticut Health Center, Farmington, CT, USA
| | - Raul J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd, Universidad de Málaga, Málaga, Spain
| | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, IN, USA.
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Cornberg M, Lok ASF, Terrault NA, Zoulim F. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference ‡. J Hepatol 2020; 72:539-557. [PMID: 31730789 DOI: 10.1016/j.jhep.2019.11.003] [Citation(s) in RCA: 224] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 10/07/2019] [Accepted: 11/03/2019] [Indexed: 12/11/2022]
Abstract
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV 'functional cure', the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
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Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany; Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
| | - Anna Suk-Fong Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Norah A Terrault
- Division of Gastrointestinal and Liver Diseases, Keck Medicine at University of Southern California, Los Angeles, CA, USA
| | - Fabien Zoulim
- Hepatology Department, Hospices Civils de Lyon, INSERM U1052, University of Lyon, France
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Palmer M, Regev A, Lindor K, Avigan MI, Dimick‐Santos L, Treem W, Marcinak JF, Lewis JH, Anania FA, Seekins D, Shneider BL, Chalasani N. Consensus guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease. Aliment Pharmacol Ther 2020; 51:90-109. [PMID: 31762074 PMCID: PMC6972572 DOI: 10.1111/apt.15579] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/03/2019] [Accepted: 10/19/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug-induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. AIMS To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases - Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). METHODS This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in-depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI-related issues occurring during clinical trials for cholestatic liver diseases. RESULTS Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. CONCLUSIONS This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.
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11
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Cornberg M, Lok ASF, Terrault NA, Zoulim F. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. Hepatology 2019; 71:1070-1092. [PMID: 31713892 DOI: 10.1002/hep.31030] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilizing cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase 3 trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss, 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity in predicting sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive and HBeAg-negative chronic hepatitis, treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with increase in bilirubin or INR should prompt temporary or permanent cessation of investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase 3 trials for hepatitis D virus (HDV) co-infection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalization of ALT is considered an intermediate goal. CONCLUSION: For HBV 'functional cure', sustained HBsAg loss with undetectable HBV DNA after completion of treatment is the primary goal and sustained undetectable HBV DNA without HBsAg loss after stopping treatment an intermediate goal.
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Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
- Centre for Individualised Infection Medicine (CiiM), Hannover, Germany
| | - Anna Suk-Fong Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Norah A Terrault
- Division of Gastrointestinal and Liver Diseases, Keck Medicine at University of Southern California, Los Angeles, CA, USA
| | - Fabien Zoulim
- Hepatology Department, Hospices Civils de Lyon, INSERM U1052, University of Lyon, France
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Andrade RJ, Aithal GP, Björnsson ES, Kaplowitz N, Kullak-Ublick GA, Larrey D, Karlsen TH. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol 2019; 70:1222-1261. [PMID: 30926241 DOI: 10.1016/j.jhep.2019.02.014] [Citation(s) in RCA: 645] [Impact Index Per Article: 107.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 02/07/2023]
Abstract
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
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Regev A, Palmer M, Avigan MI, Dimick‐Santos L, Treem WR, Marcinak JF, Seekins D, Krishna G, Anania FA, Freston JW, Lewis JH, Sanyal AJ, Chalasani N. Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2019; 49:702-713. [PMID: 30761572 PMCID: PMC6593464 DOI: 10.1111/apt.15153] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/22/2018] [Accepted: 01/02/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. AIMS This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. METHODS This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. RESULTS Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. CONCLUSIONS This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.
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Brott DA, Goodman MJ, Hermann RP, Merz M, Calvo R, Poorkhalkali N, Kiazand A. Are laboratory parameter (biomarker) values similar to the healthy volunteer reference range in all patient populations? Drug Des Devel Ther 2018; 12:2757-2773. [PMID: 30233139 PMCID: PMC6132491 DOI: 10.2147/dddt.s173671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Liver biomarkers alanine aminotransferase (ALT) and bilirubin in patients with hepatitis are above the healthy volunteer reference range (HVRR) at baseline (prior to receiving the clinical trial medication). Discussions continue as how to best distinguish drug-induced liver injury in patients with abnormal baseline values participating in clinical trials. This study investigated if other baseline routine clinical safety biomarkers (lab parameters) are different from the HVRR. Materials and methods Clinical trial data (TransCelerate dataset) from placebo and standard of care treated patients were compared to the HVRR using a 10% threshold above or below the HVRR to classify a lab parameter in a patient population as potentially different from the HVRR at baseline. The TransCelerate dataset, batch 4, contained data from patients with Alzheimer’s, asthma, COPD, cardiovascular disease, diabetes, hidradenitis, hypercholesterolemia, rheumatoid arthritis, schizophrenia, stroke, and ulcerative colitis. A subset of the 200 biomarkers in Trans-Celerate were evaluated in this pilot: glucose, platelet count, neutrophil count, ALT, aspartate aminotransferase (AST), and bilirubin. Results Glucose was potentially higher than the HVRR in patients with diabetes, COPD, cardiovascular disease, hypercholesterolemia, and schizophrenia. At least one or more of the hematology and hepatic biomarkers were different from the HVRR in at least one patient population, except bilirubin. All the patient populations, except Alzheimer’s and asthma, had at least one biomarker that was higher than the HVRR. Summary The routine biomarkers evaluated in this pilot study demonstrated that not all lab parameters in patient populations are similar to the HVRR. Further efforts are needed to determine which biomarkers are different from the HVRR and how to evaluate the biomarkers in patient populations for detecting drug-induced altered lab values in clinical trials.
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Affiliation(s)
- David A Brott
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | - Michael J Goodman
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | - Richard P Hermann
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | - Michael Merz
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Webel, Germany
| | - Roser Calvo
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | | | - Alexandre Kiazand
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
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Benesic A, Rotter I, Dragoi D, Weber S, Leitl A, Buchholtz ML, Gerbes AL. Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury. Clin Gastroenterol Hepatol 2018; 16:1488-1494.e5. [PMID: 29723689 DOI: 10.1016/j.cgh.2018.04.049] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 04/08/2018] [Accepted: 04/20/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an in vitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance. METHODS We performed a prospective study of patients referred to the University Hospital in Munich, Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory test and imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10 days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests. RESULTS Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanate to cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results). CONCLUSIONS We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT 02353455.
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Affiliation(s)
- Andreas Benesic
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany.
| | - Isabelle Rotter
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
| | - Diana Dragoi
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany
| | - Sabine Weber
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
| | | | - Marie-Luise Buchholtz
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilians-Universität Munich, Germany
| | - Alexander L Gerbes
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
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García-Cortés M, Ortega-Alonso A, Lucena MI, Andrade RJ. Drug-induced liver injury: a safety review. Expert Opin Drug Saf 2018; 17:795-804. [PMID: 30059261 DOI: 10.1080/14740338.2018.1505861] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Idiosyncratic drug-induced liver injury (DILI) remains one of the most important causes of drug attrition both in the early phases of clinical drug development and in the postmarketing scenario. This is because, in spite of emerging data on genetic susceptibility variants associated to the risk of hepatotoxicity, the precise identification of the individual who will develop DILI when exposed to a given drug remains elusive. AREAS COVERED In this review, we have addressed recent progress made and initiatives taken in the field of DILI from a safety perspective through a comprehensive search of the literature. EXPERT OPINION Despite the substantial progress made over this century, new approaches using big data analysis to characterize the true incidence of DILI are needed and to categorize the drugs' hepatotoxic potential. Genetic studies have highlighted the role of the adaptive immune system yet the mechanisms leading adaptation versus progression remain to be elucidated. There is a compelling need for development and qualification of sensitive, specific, and affordable biomarkers in DILI to foster drug development, patient treatment stratification and, improvement of causality assessment methods. Gaining mechanistic insights in DILI is essential to uncover therapeutic targets and design prospective clinical trials with appropriate endpoints.
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Affiliation(s)
- Miren García-Cortés
- a Instituto de Investigación Biomédica-IBIMA , Hospital Universitario Virgen de la Victoria, Universidad de Málaga , Málaga , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain
| | - Aida Ortega-Alonso
- a Instituto de Investigación Biomédica-IBIMA , Hospital Universitario Virgen de la Victoria, Universidad de Málaga , Málaga , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain
| | - M Isabel Lucena
- b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain.,c Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria , Universidad de Málaga , Málaga , Spain
| | - Raúl J Andrade
- a Instituto de Investigación Biomédica-IBIMA , Hospital Universitario Virgen de la Victoria, Universidad de Málaga , Málaga , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain
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Avigan MI, Muñoz MA. Perspectives on the Regulatory and Clinical Science of Drug-Induced Liver Injury (DILI). METHODS IN PHARMACOLOGY AND TOXICOLOGY 2018. [DOI: 10.1007/978-1-4939-7677-5_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Teschke R, Danan G. Diagnosis and Management of Drug-Induced Liver Injury (DILI) in Patients with Pre-Existing Liver Disease. Drug Saf 2017; 39:729-44. [PMID: 27091053 DOI: 10.1007/s40264-016-0423-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The relationship between drugs and pre-existing liver disease is complex, particularly when increased liver tests (LTs) or new symptoms emerge in patients with pre-existing liver disease during drug therapy. This requires two strategies to assess whether these changes are due to drug-induced liver injury (DILI) as a new event or due to flares of the underlying liver disease. Lacking a valid diagnostic biomarker, DILI is a diagnosis of exclusion and requires causality assessment by RUCAM, the Roussel Uclaf Causality Assessment Method, to establish an individual causality grading of the suspected drug(s). Flares of pre-existing liver disease can reliably be assessed in some hepatotropic virus infections by polymerase chain reaction (PCR) and antibody titers at the beginning and in the clinical course to ascertain flares during the natural course of the disease. Unfortunately, flares cannot be verified in many other liver diseases such as alcoholic liver disease, since specific tests are unavailable. However, such a diagnostic approach using RUCAM applied to suspected DILI cases includes clinical and biological markers of pre-existing liver diseases and would determine whether drugs or underlying liver diseases caused the LT abnormalities or the new symptoms. More importantly, a clear diagnosis is essential to ensure effective disease management by drug cessation or specific treatment of the flare up due to the underlying disease.
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Affiliation(s)
- Rolf Teschke
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, Klinikum Hanau, Leimenstrasse 20, 63450, Hanau, Germany. .,Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Frankfurt/Main, Germany.
| | - Gaby Danan
- Pharmacovigilance Consultancy, Paris, France
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Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut 2017; 66:1154-1164. [PMID: 28341748 PMCID: PMC5532458 DOI: 10.1136/gutjnl-2016-313369] [Citation(s) in RCA: 317] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 02/24/2017] [Accepted: 02/28/2017] [Indexed: 12/12/2022]
Abstract
Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships.
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Affiliation(s)
- Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich and University of Zurich, Zurich, Switzerland,Drug Safety and Epidemiology, Novartis Pharma, Basel, Switzerland
| | - Raul J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain
| | - Michael Merz
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Peter End
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Andreas Benesic
- Department of Medicine II, Klinikum Grosshadern of the University of Munich (KUM), University of Munich, Munich, Germany,MetaHeps GmbH, Planegg/Martinsried, Germany
| | - Alexander L Gerbes
- Department of Medicine II, Klinikum Grosshadern of the University of Munich (KUM), University of Munich, Munich, Germany
| | - Guruprasad P Aithal
- National Institute for Health Research (NIHR), Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
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Teschke R, Danan G. Drug-induced liver injury: Is chronic liver disease a risk factor and a clinical issue? Expert Opin Drug Metab Toxicol 2016; 13:425-438. [PMID: 27822971 DOI: 10.1080/17425255.2017.1252749] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Clinicians and practitioners caring for patients with chronic liver disease are often unsure whether drug therapy is a hazard that increases their patient's risk for drug-induced liver injury (DILI). Areas covered: We searched for reports of drug induced liver injury, both idiosyncratic and intrinsic, in patients with chronic liver disease including non-alcoholic and alcoholic liver disease, and cirrhosis. Reports we analyzed include statin treatment in patients with fatty liver, acetaminophen use in alcoholic fatty liver, antituberculous drugs in patients with tuberculosis and viral hepatitis, antiviral medications in hepatitis and antiretroviral medications in HIV/AIDS. The most challenging cases we found are drug therapy in patients with decompensated liver cirrhosis. Expert opinion: We identified many case reports and case series discussing a potential increased risk of DILI in patients with pre-existing liver disease. However, most of these reports were retrospective and ambiguous. With few exceptions, we conclude that drugs seem to be well tolerated by the majority of patients with pre-existing, non-cirrhotic chronic liver diseases. Special care is needed for some therapies, however, including antiviral therapy in chronic hepatitis B and C and in decompensated liver cirrhosis with impaired drug metabolism. Prospective studies are warranted to valid our conclusions.
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Affiliation(s)
- Rolf Teschke
- a Department of Internal Medicine II , Division of Gastroenterology and Hepatology , Klinikum Hanau , Hanau , Germany.,b Academic Teaching Hospital of the Medical Faculty , Goethe University Frankfurt/Main , Frankfurt/Main , Germany
| | - Gaby Danan
- c Pharmacovigilance Consultancy , Paris , France
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21
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Benesic A, Leitl A, Gerbes AL. Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut 2016; 65:1555-63. [PMID: 26045135 DOI: 10.1136/gutjnl-2015-309528] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 05/08/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Idiosyncratic drug-induced liver injury (iDILI) is a frequent cause of acute liver injury and a serious problem in late stage drug-development. Its diagnosis is one of the most challenging in hepatology, since it is done by exclusion and relies on expert opinion. Until now no reliable in vitro test exists to support the diagnosis of iDILI. In some instances it is impossible to determine the causative drug in polymedicated patients. AIM To investigate if monocyte-derived hepatocyte-like (MH) cells might be a tool supporting clinical judgment for iDILI diagnosis and causality assessment. METHODS This prospective study included 54 patients with acute liver injury and intake of at least one drug. Thirty-one patients were diagnosed with iDILI based on causality likelihood. MH cells were generated from every patient and in vitro toxicity of the respective drugs was assessed by lactate-dehydrogenase release. The results from MH cells and RUCAM, the most widely used scoring system as methods to support clinical judgement were compared. RESULTS MH cells showed enhanced toxicity in 29 of the 31 patients with iDILI, similar to RUCAM score. MH cells exhibited negative results in the 23 non-DILI cases, whereas RUCAM indicated possible iDILI in six cases. Analysis of the comedications also showed superior specificity of MH cells. No MH cell toxicity of the drugs showing toxicity in patients with iDILI was observed in MH cells of healthy donors. CONCLUSIONS In this pilot study in vitro testing using MH cells derived from patients with acute liver injury was able to identify patients with iDILI with an excellent sensitivity and a higher specificity than RUCAM, the most widely used current causality assessment score. Therefore, MH cells could be useful to identify the causative drugs even in polymedicated patients by adding objective data to causality assessment. TRIAL REGISTRATION NUMBER NCT02353455.
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Affiliation(s)
- Andreas Benesic
- Liver Center Munich, Department of Internal Medicine II, University Hospital Munich, Campus Grosshadern, Munich, Germany MetaHeps GmbH, Planegg/Martinsried, Germany
| | - Alexandra Leitl
- Liver Center Munich, Department of Internal Medicine II, University Hospital Munich, Campus Grosshadern, Munich, Germany
| | - Alexander L Gerbes
- Liver Center Munich, Department of Internal Medicine II, University Hospital Munich, Campus Grosshadern, Munich, Germany
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Lewis JH. The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond. Clin Gastroenterol Hepatol 2015; 13:2173-89.e8. [PMID: 26116527 DOI: 10.1016/j.cgh.2015.06.017] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 06/15/2015] [Accepted: 06/15/2015] [Indexed: 12/13/2022]
Abstract
Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50-100 mg is more likely to be hepatotoxic than does <10 mg, especially if the compound is highly lipophilic or undergoes extensive hepatic metabolism. The quest for a predictive biomarker to replace alanine aminotransferase is ongoing. Markers of necrosis and apoptosis such as microRNA-122 and keratin 18 may prove useful in identifying patients at risk for severe injury when they initially present with a suspected acetaminophen overdose. Although a number of drugs causing idiosyncratic DILI have HLA associations that may allow for pre-prescription testing to prevent hepatotoxicity, the cost and relatively low frequency of injury among affected patients limit the current usefulness of such genome-wide association studies. Alanine aminotransferase monitoring is often recommended but has rarely been shown to be an effective method to prevent serious DILI. Guidelines on the diagnosis and management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike.
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Affiliation(s)
- James H Lewis
- Hepatology Section, Division of Gastroenterology, Georgetown University Hospital, Washington, District of Columbia.
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Raschi E, De Ponti F. Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of post-marketing risk. World J Hepatol 2015; 7:1761-1771. [PMID: 26167249 PMCID: PMC4491905 DOI: 10.4254/wjh.v7.i13.1761] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/21/2015] [Accepted: 06/18/2015] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) and herb-induced liver injury is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications in the past 15 years. This review will first provide clues for clinicians to suspect idiosyncratic (unpredictable) DILI and succeed in diagnosis. Causality assessment remains challenging and requires careful medical history as well as awareness of multifaceted aspects, especially for herbs. Drug discontinuation and therapy reconciliation remain the mainstay in patent's management to minimize occurrence of acute liver failure. The second section will address novel agents associated with liver injury in 2014 (referred to as "signals"), especially in terms of clinical, research and drug development implications. Insights will be provided into recent trends by highlighting the contribution of different post-marketing data, especially registries and spontaneous reporting systems. This literature scrutiny suggests: (1) the importance of post-marketing databases as tools of clinical evidence to detect signals of DILI risk; and (2) the need for joining efforts in improving predictivity of pre-clinical assays, continuing post-marketing surveillance and design ad hoc post-authorization safety studies. In this context, ongoing European/United States research consortia and novel pharmaco-epidemiological tools (e.g., specialist prescription event monitoring) will support innovation in this field. Direct oral anticoagulants and herbal/dietary supplements appear as key research priorities.
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Affiliation(s)
- Emanuel Raschi
- Emanuel Raschi, Fabrizio De Ponti, Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, I-40126 Bologna, Italy
| | - Fabrizio De Ponti
- Emanuel Raschi, Fabrizio De Ponti, Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, I-40126 Bologna, Italy
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Liver safety assessment: required data elements and best practices for data collection and standardization in clinical trials. Drug Saf 2015; 37 Suppl 1:S19-31. [PMID: 25352325 PMCID: PMC4212151 DOI: 10.1007/s40264-014-0183-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. In a breakout session, workshop attendees discussed necessary data elements and standards for the accurate measurement of DILI risk associated with new therapeutic agents in clinical trials. There was agreement that in order to achieve this goal the systematic acquisition of protocol-specified clinical measures and lab specimens from all study subjects is crucial. In addition, standard DILI terms that address the diverse clinical and pathologic signatures of DILI were considered essential. There was a strong consensus that clinical and lab analyses necessary for the evaluation of cases of acute liver injury should be consistent with the US Food and Drug Administration (FDA) guidance on pre-marketing risk assessment of DILI in clinical trials issued in 2009. A recommendation that liver injury case review and management be guided by clinicians with hepatologic expertise was made. Of note, there was agreement that emerging DILI signals should prompt the systematic collection of candidate pharmacogenomic, proteomic and/or metabonomic biomarkers from all study subjects. The use of emerging standardized clinical terminology, CRFs and graphic tools for data review to enable harmonization across clinical trials was strongly encouraged. Many of the recommendations made in the breakout session are in alignment with those made in the other parallel sessions on methodology to assess clinical liver safety data, causality assessment for suspected DILI, and liver safety assessment in special populations (hepatitis B, C, and oncology trials). Nonetheless, a few outstanding issues remain for future consideration.
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Weiler S, Merz M, Kullak-Ublick GA. Drug-induced liver injury: the dawn of biomarkers? F1000PRIME REPORTS 2015; 7:34. [PMID: 25926985 PMCID: PMC4371234 DOI: 10.12703/p7-34] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Drug-induced liver injury (DILI) is a potentially fatal adverse event with significant medical and economic impact. Many drugs, especially anti-infective, neurologic or pain-modifying substances, act as hepatotoxins. With cardiovascular toxicity, liver toxicity is one of the two leading causes for drug withdrawal from the market. The liver can be affected directly, in a predictable and dose-dependent manner, or idiosyncratically, independent of the dose and therefore unpredictable. Currently DILI is a diagnosis of exclusion that physicians have to bear in mind in patients with an unexplained increase of liver enzymes. The type of injury is categorized into hepatocellular, cholestatic, or mixed by the respective enzyme pattern of injury. Symptoms of affected patients can mimic any other liver disease. Therefore, new diagnostic and prognostic biomarkers for early liver injury are currently being evaluated in multi-centre clinical trials that are conducted by international consortia and other initiatives. Pharmacogenetic testing, next-generation sequencing, proteomics, metabolomics and mechanistic markers can help to preselect susceptible patient populations and tailor drug therapy to individual patients. Proposed DILI indicators that are under investigation include microRNAs, cytokeratin-18 (CK18), high mobility group box protein 1 (HMGB-1), and several other biomarkers. These developments can change clinical practice, and improve patients' safety and management. However, they have not been translated into clinical practice or approved for routine use yet. Management of DILI usually consists of initial withdrawal of the suspected drug and—if applicable—administration of specific antidotes, such as N-acetylcysteine. However, the overall management of DILI could change in the near future with the advent of novel diagnostic and prognostic DILI markers.
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Affiliation(s)
- Stefan Weiler
- Department of Clinical Pharmacology and Toxicology, University Hospital ZurichRaemistrasse 100, CH-8091 ZurichSwitzerland
| | - Michael Merz
- Discovery and Investigative Safety, Novartis Institutes for BioMedical ResearchKlybeckstrasse 141, 4057 BaselSwitzerland
| | - Gerd A. Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital ZurichRaemistrasse 100, CH-8091 ZurichSwitzerland
- Discovery and Investigative Safety, Novartis Institutes for BioMedical ResearchKlybeckstrasse 141, 4057 BaselSwitzerland
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