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Sharing Information, asking questions – liver safety data warehouse? March 15, 2012 Paul B. Watkins The Hamner-University of North Carolina Institute for Drug Safety Sciences Reasons why drugs are withdrawn from the market Cardiovascular 12% Torsade de Pointes 33% Hepatotoxicity Hepatotoxicity 32% 32% GI 2% Immunotox 2% Nervous System 2% Other 8% HaematologyBM 9% Drug Discov Today 14, 162-167,2009 Drug-induced Liver Injury Many different forms of liver injury… The biggest problem in drug development is: Acute Idiosyncratic Hepatocellular Injury Course of LiverHepatocellular Tests Typical Acute Time Idiosyncratic Injury Patient #1234, caucasian male 80, Drug X 100.0 10.0 died ALTx TBLx ASTx ALPx 1.0 probably drug-induced hosp Study Day Courtesy John Senior Courtesy John Senior 180 150 120 90 60 30 0 0.1 -30 Liver Test Values, xULRR Acute Idiosyncratic Hepatotocellular start stop Injury (AIHI) Drugs causing ALT elevations > 3 X ULN and low risk of DILI Drug Incidence Jaundice Tacrine ~25% no cases Statins 1-3% <1:100,000 Heparins ~15% no cases In contrast: Troglitazone 1.5% ~1:1,000 NEJM, 338(13) 916-7,1998. 4 Course of LiverHepatocellular Tests Typical Acute Time Idiosyncratic Injury Patient #1234, caucasian male 80, Drug X 100.0 Hy’s Law 10.0 died ALTx TBLx ASTx ALPx 1.0 probably drug-induced hosp Study Day Courtesy John Senior Courtesy John Senior 180 150 120 90 60 30 0 0.1 -30 Liver Test Values, xULRR Acute Idiosyncratic Hepatotocellular start stop Injury (AIHI) Research priority New clinical tests that can: Distinguish ALT/AST elevations that are benign vs. those associated with clinically important liver injury before the subject is at any risk. Initial strategy to find better DILI biomakers Fully characterize biomarkers during ALT elevations that that are benign and are clinically unimportant. 7 Nine healthy medical students given unfractionated heparin 5000 U q 8 hr s.c. for 20 days ALT elevations resolve through continued treatment 8 Study of heparins and liver toxicity 1. Heparins have never been reported to cause ALT or AST elevations or histological liver injury in rodents or dogs – “human specific”. 2. Proposed mechanism underlying ALT/AST elevations include non hepatic enzyme sources, reduced plasma clearance and enzyme induction. 9 Heparin Study Protocol 4 Heparin types administered BID s.c. – 9 doses total Healthy non-smoking subjects, males, age 18-50 yrs Heparin Unfractionated heparin Enoxaparin sodium Dalteparin sodium Adomiparin sodium (M118) Type Unfractionated Low molecular weight Low molecular weight Low molecular weight Dose 150 U/kg 1 mg/kg (100 IU/kg) 120 IU/kg (maximum of 10,000 IU) 125 IU/kg Treatment Scheme Day -1 •Check in Blood Day 1 • Dose 2x daily Blood Day 2 Day 3 Day 4 Day 5 •Dose 2x daily •Dose 2x daily •Dose 2x daily •Dose 1x Blood Blood Blood Blood Day 6 •Follow up Blood Day 7 •Follow up Blood Day 12 •Follow up Blood Clin. Pharmacol. Ther. In Press Day 33 •Follow up Per Subject ALT Elevations Treatment Clin. Pharmacol. Ther. In Press HMGB1 HMGB1 Treatment (necrosis) miR-122 miR-122 (liver specific) Clin. Pharmacol. Ther. In Press 12 HMGB1 – HMGB1 is a known damage associated molecular pattern (DAMP) released from necrotic cells – bridges cell death to the inflammatory response – Innate immune cells (Kupffer cells) secrete acetylated HMGB1 13 Acetylated HMGB1 (fold change from own baseline) Fold change from own baseline 50 UFH Enoxaparin Dalteparin M118 40 30 20 10 0 0.5hr0 Day 95.5hr Day 5 144hr7 Day time point Clin. Pharmacol. Ther. In Press Slide: Dan Antoine HMGB1 nonacetylated acetylated Treatment miR-122 miR-122 Clin. Pharmacol. Ther. In Press 15 Conclusions 1). Heparins cause hepatocyte necrosis and this may involve both a direct and indirect effect 2). The indirect necrotic process may be due to an inflammatory response. 3). Why heparins are safe for the liver is not clear. 4). Identification and validation of improved DILI biomarkers will be a challenge 16 What should a responsible drug company be doing? Standardized liver safety data management tools should be adopted. 17 eDISH – evaluation of Drug-Induced Serious Hepatotoxcity 100.0 hyperbilirubinemia Hy's Law range Peak TBL, xULRR Drug X Drug C 10.0 2x 1.0 normal range 0.1 0.1 3x Temple's Corollary range 1.0 10.0 100.0 Peak ALT, xULRR Drug Safety,34(3)243-52, 2011 18 Time Course of Liver Tests Patient #1234, caucasian male 80, Drug X 100.0 10.0 died ALTx TBLx ASTx ALPx 1.0 probably drug-induced hosp Study Day Courtesy John Senior Courtesy John Senior 180 150 120 90 60 30 0 0.1 -30 Liver Test Values, xULRR Acute Idiosyncratic Hepatotocellular start stop Injury (AIHI) eDISH becoming standard for liver safety review • • The eDISH-Data Requirement in MS® Excel format (a Excel workbook including 4 worksheets) is made available for the sponsor. We adopt the standard terms and terminologies of CDISC/SDTM as we see fit; and improve them to best serve the evaluation of DILI. A portion of eDISH Home page: from Ted Guo - FDA Liver Safety Data Warehouse exists: • The eDISH account management system (controlled by eDISH developers): – Create storage space for every drug we reviewed – Create and maintain accounts for eDISH users (FDA medical reviewers) – Instruct eDISH users how to sign-in the eDISH system • Standardized and eDISH-review ready data as SAS datasets are maintained on a FDA server from Ted Guo - FDA more … ECG Warehouse Standardized ECG format - Norman Stockbridge Creation of the Cardiac Research Safety Consortium in 2006 Should a similar path now be followed for liver safety? 22 eDISH would also provide a means of organizing biobanks 23 Time Course of Liver Tests Patient #1234, caucasian male 80, Drug X 100.0 10.0 died ALTx TBLx ASTx ALPx 1.0 probably drug-induced hosp Study Day Courtesy John Senior Courtesy John Senior 180 150 120 90 60 30 0 0.1 -30 Liver Test Values, xULRR Acute Idiosyncratic Hepatotocellular start stop Injury (AIHI) Summary 1). New liver safety biomarkers are coming soon. 2). They may save drugs with ALT signals. 3). The industy should adopt standard liver safety data and biospecimen management tools 4). These tools would greatly facilitate future precompetitive efforts to discover and validate better DILI biomarkers 25 Thanks Hamner-UNC IDSS Alison Harrill, Scott Eady Momenta Jim Roach Ian Fier Liverpool Kevin Park Daniel Antoine FDA Ted Guo