Global Product Patient Safety Biomarkers for DILI: Moving from Preclinical to Clinical Studies Arie Regev, M.D. Global Patient Safety Eli Lilly and Company Indianapolis, IN
New IDILI Biomarkers in the Clinic: State of the Art Number of new IDILI biomarkers in clinical practice in the last 40 years: Number of new IDILI biomarkers currently in clinical development: Number of drugs for which IDILI mechanism is completely understood: Number of widely accepted animal models for IDILI: 0 0 0 0 Number of clinicians and basic-research scientists who agree with each other on IDILI biomarkers: Too Low
Conditions for Success of Future Translational Work on DILI Biomarkers 1. Understand the types of DILI in humans and their diverse clinical presentation 2. Focus on the questions that IDILI biomarkers need to address in the clinic 3. Know the limitations of animal studies and in-vitro models in the study of IDILI 4. Know the clinical strengths and shortcomings of existing DILI biomarkers (e.g. ALT, AST, AlkP, TBIL, GGT, etc.) 5. Continue communication between preclinical scientists and clinicians throughout the biomarker development process
Blind Men and an Elephant
Blind Men and an Elephant It s an elephant It s an elephant It s an elephant It s an elephant
DILI- Not a Single Entity Dose Dependent DILI Idiosyncratic DILI Isoniazid Amoxicillin-Clavulanate Methotrexate Main biomarker- ALT Main biomarker- AlkP Main biomarker-?
ALT in Methotrexate induced Liver Injury No significant differences in ALT or AST between patients that developed severe liver fibrosis and those that did not. Rosenberg, J Hepatol 2007;46:111-8 Berends, Aliment Pharmacol Ther 2006;24:805 811
DILI- Not a Single Entity (Cont ) Amoxicillin-Clavulanate induced Cholestatic injury Amoxicillin-Clavulanate induced Hepatocellular injury? Hepatocellular DILI due to drug X in patient A Hepatocellular DILI due to drug X in patient B?
Conditions for Success of Future Translational Work on DILI Biomarkers 1. Understand the types of DILI in humans and their diverse clinical presentation 2. Focus on the questions that IDILI biomarkers need to address in the clinic 3. Know the limitations of animal studies and in-vitro models in the study of IDILI 4. Know the clinical strengths and shortcomings of existing DILI biomarkers (e.g. ALT, AST, AlkP, TBIL, GGT, etc.) 5. Continue communication between preclinical scientists and clinicians throughout the biomarker development process
Potential Roles for Biomarkers in Hepatocellular DILI (I) 1. Detection of susceptibility to DILI (susceptibles vs tolerators/adaptors) during early drug development N/A Hy s Rule prior to exposure N/A during drug treatment N/A N/A 2. Identifying drugs capable of causing severe DILI
Potential Roles for Biomarkers in Hepatocellular DILI (II) 1. Detection of liver injury at an early injury stage in a mild injury 2. Differentiation of liver injury from injuries of other organs (e.g. muscle) ALT ALT 3. Differentiation of significant liver injury from transient ALT changes (susceptibles vs. tolerators/adaptors) 4. Prediction of severe outcome (live failure) Hepatocellular DILI!! ALT/AST, N/A CPK Liver-specific mrna 1,2 N/A 5. Differentiate DILI from other causes of liver injury N/A N/A 1. Miyamoto et al. Toxicological Sciences 2008;106:538 2. Wetmore et al. Hepatology. 2010;51:2127-39
Conditions for Success of Future Translational Work on DILI Biomarkers 1. Understand the types of DILI in humans and their diverse clinical presentation 2. Focus on the questions that IDILI biomarkers need to address in the clinic 3. Know the limitations of animal studies and in-vitro models in the study of IDILI 4. Know the clinical strengths and shortcomings of existing DILI biomarkers (e.g. ALT, AST, AlkP, TBIL, GGT, etc.) 5. Continue communication between preclinical scientists and clinicians throughout the biomarker development process
Multinational pharmaceutical company survey 12 pharmaceutical companies, 150 compounds Examined the percentage of human drug toxicities that had previously occurred in animal studies
Animal Concordance by Human Toxicity Category. Olson et al. Regulatory Toxicology and Pharmacology 2000; 32: 56 67
Company Confidential Copyright 2007 Eli Lilly and Company
Conditions for Success of Future Translational Work on DILI Biomarkers 1. Understand the types of DILI in humans and their diverse clinical presentation 2. Focus on the questions that IDILI biomarkers need to address in the clinic 3. Know the limitations of animal studies and in-vitro models in the study of IDILI 4. Know the clinical strengths and shortcomings of existing DILI biomarkers (e.g. ALT, AST, AlkP, TBIL, GGT, etc.) 5. Continue communication between preclinical scientists and clinicians throughout the biomarker development process
Is ALT a Gold Standard? ALT
Is ALT a Gold Standard?
Vector Analysis to Detect Hepatotoxicity Signals The ALT Worship Trost, Freston. Drug Information Journal 2008;42:27-34
ALT Levels in Patients with Idiosyncratic DILI (2)
ALT Levels in Patients with Idiosyncratic DILI (2) Mindikoglu, Magder, Regev. Liver Transplantation 2009; 15:719-729
Kechagias et al. Gut 2008
Conditions for Success of Future Translational Work on DILI Biomarkers 1. Understand the types of DILI in humans and their diverse clinical presentation 2. Focus on the questions that IDILI biomarkers need to address in the clinic 3. Know the limitations of animal studies and in-vitro models in the study of IDILI 4. Know the clinical strengths and shortcomings of existing DILI biomarkers (e.g. ALT, AST, AlkP, TBIL, GGT, etc.) 5. Continue communication between preclinical scientists and clinicians throughout the biomarker development process
Summary: Conditions for Success of Future Translational Work on DILI Biomarkers 1. Understand the types of DILI in humans and their diverse clinical presentation 2. Focus on the questions that IDILI biomarkers need to address in the clinic 3. Know the limitations of animal studies and in-vitro models in the study of IDILI 4. Know the clinical strengths and shortcomings of existing DILI biomarkers (e.g. ALT, AST, AlkP, TBIL, GGT, etc.) 5. Continue communication between preclinical scientists and clinicians throughout the biomarker development process
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