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Drug Induced Liver Injury: Implications in drug discovery and development

Drug Induced Liver Injury: Implications in drug discovery and development. Paul B. Watkins University of North Carolina Chapel Hill, N.C. Drug Induced Liver Injury (DILI) is Hot. FDA / Pharma steering committee Several Critical Path Initiatives $ millions spend in industry

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Drug Induced Liver Injury: Implications in drug discovery and development

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  1. Drug Induced Liver Injury: Implications in drug discovery and development Paul B. Watkins University of North Carolina Chapel Hill, N.C.

  2. Drug Induced Liver Injury (DILI) is Hot FDA / Pharma steering committee Several Critical Path Initiatives $ millions spend in industry New Network (DILIN) SAE Consortium

  3. Industry SAE Priorities 2006Rank Order [1 highest to 5 lowest] SAE Consortium Survey – courtesy of Arthur Holden

  4. Troglitazone (Rezulin®) 1). PPARg agonist 2). Treats type 2 diabetes 3). Caused liver failure

  5. Presentation by Dr. Mark Pierce (Parke-Davis Pharmaceutical Research) Overall Post-Marketing Reporting Death/Transplant Rate March 1997 - March 1999 35 in 1.58 million = 1 in 45,098 Background incidence of liver failure with no known cause ~ 1 in 1 million March 26th 1999 - Troglitazone - FDA Advisory Panel

  6. Troglitazone (Rezulin®) 1). Acute liver failure reports continued despite warnings and monitoring recommendations 2). Second in class (2) came on the market and appeared to be safer 3). Withdrawn from the market

  7. Troglitazone (Rezulin®) The Rise and Fall of the Killer Drug RezulinLos Angeles Times, June 4, 2000, p.1A. “…a disparate collection of physicians inside the U.S. Food and Drug Administration waged a remarkable revolt that … combined meticulous research and bluntly worded e-mail messages to upbraid their government superiors for contributing to the needless deaths of patients.”

  8. Why clinical drug development programs were terminated in 1991 % of total terminations Nature Reviews: Drug Discovery, Aug, 2004

  9. Why clinical drug development programs were terminated in 2000 % of total terminations 1991 2000 Nature Reviews: Drug Discovery, Aug, 2004

  10. “Hepatotoxicity has been the most common single adverse effect causing major drug problems, including withdrawals and refusals to approve” Bob Temple, M.D. FDA 2/15/01

  11. 2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures

  12. Compound Pair Ibuprofen “Clean” Compound Ibufenac “Toxic” Compound* *withdrawn from the market in the 1960’s because of clinical liver toxicity

  13. 2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures 2). Target daily dose to < 10 mg/day

  14. 2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures 2). Target daily dose to < 10 mg/day 3). Low covalent binding in liver microsomes 4). Low production of glutathione conjugates

  15. 2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures 2). Target daily dose to < 10 mg/day 3). Low covalent binding in liver microsomes 4). Low production of glutathione conjugates 5). Low incidence (<5%) of ALT > 3 X ULN in clinical trials.

  16. Example: Acetaminophen 1). Avoid certain molecular structures - NO 2). Target daily dose to < 10 mg/day – 4 grams/day 3). Low covalent binding in liver microsomes – NO 4). Low production of glutathione conjugates – NO 5). Low incidence (<5%) of ALT - NO

  17. JAMA, 392:87,2006

  18. Example: Acetaminophen 1). Avoid certain molecular structures - NO 2). Target daily dose to < 10 mg/day – 4 grams/day 3). Low covalent binding in liver microsomes – NO 4). Low production of glutathione conjugates – NO 5). Low incidence (<5%) of ALT - NO

  19. Drug Induced Liver Injury (DILI) 1). Thorn in the side of drug development. 2). High priority to design out of drugs. 3). Little progress made to date.

  20. Drug Induced Liver Injury (DILI) can mimick every known liver disease Cholestasis (&vanishing bile duct syndrome) Steatosis (micro and macrovesicular) Phospholipidosis Veno-occlusive disease Occult fibrosis/ cirrhosis Liver cancer Acute hepatocellular injury – High ALT/AST

  21. Regulatory actions due to DILI (1995-2006) Withdrawals bromfenac troglitazone pemoline Warnings acetaminophen leflunomide nefazodone nevirapine pyrazinamide/rifampin terbinafine valproic acid zifirlukast atomoxetine interferon 1b –1b and 1a saquinavir infliximab bosentan telithromycin (kava, lipokinex) Second Line felbamate tolcapone trovafloxacin http://www.fda.gov/medwatch/safety.htm

  22. Regulatory actions due to DILI (1995-2006) Withdrawals bromfenac troglitazone pemoline Warnings acetaminophen leflunomide nefazodone nevirapine pyrazinamide/rifampin terbinafine valproic acid zifirlukast atomoxetine interferon 1b –1b and 1a saquinavir infliximab bosentan telithromycin (kava, lipokinex) Second Line felbamate tolcapone trovafloxacin http://www.fda.gov/medwatch/safety.htm

  23. Of the 23 drugs/CAM that have undergone withdrawal, restriction or warnings 19/23 (82%) were associated with acute idiosyncratic hepatocellular injury

  24. “idiosyncracy” (Hippocrates, ~400 B.C.) (idios) - one’s own, self (syn) - together (crasis) - a mixing, mixture therefore a person’s own mixture of characteristics, factors, nature and nurture, uniquely John Senior - FDA

  25. SAFE Liver injury ( ALT) safe Concept of idiosyncratic hepatocellular injury

  26. death jaundice enceph Days on drug

  27. Challenges in identifying factors underlying susceptibility to DILI 1). How to identify susceptible individuals. 2). What to do with them once you have them.

  28. SAFE Liver injury ( ALT) safe Concept of idiosyncratic hepatocellular injury

  29. Selection of patients based on serial ALT values in a clinical trial C.V. Non-susceptible susceptible ULN

  30. A genetic test that predicts ALT elevations: 2). Would be useful in developing next in class drugs. 1). Would obviate need for ALT monitoring. 3). May provide only limited insight into mechanisms of idiosyncratic severe DILI.

  31. Problem with ALT elevation as the endpoint 1). Occurs with drugs that do not have clinically important liver toxicity 2). Usually reverse with continued treatment even with drugs that can cause acute liver failure.

  32. ALT Incidence of ALT elevations (>3X ULN) and clinical hepatitis hepatitis troglitazone 2% <0.1 INH 15% <1% diclofenac 3% <0.01%

  33. Treatment with tacrine through ALT elevations unpublished

  34. Reversed on treatment Treatment stopped unpublished

  35. Reversal of rat liver necrosis with continued exposure to BDCM 1 week 3 weeks Toxicol. Sci. 64:268 (2001)

  36. Possible explanations for reversibility of ALT elevations 1). ALT elevations that reverse on treatment have no relationship to those that can progress to liver failure. 2). A subset of those with ALT elevations can progress on to liver failure (i.e. those who can not adapt).

  37. X Progressive injury Adaptation elimination Safe pathways Reactive Metabolite Drug ALT elevations

  38. jaundice SAFE liver failure Increased ALT safe Concept of idiosyncratic hepatocellular injury

  39. safe elimination NAPQI APAP Covalent binding/oxidative stress resolution progression

  40. Effect of 8 days APAP pretreatment (---) on single dose toxicity in mice Hepatology 29:436, 1999.

  41. 3-Cys-APAP adducts (brown) 2 hours after single toxic APAP dose Saline pretreatment APAP pretreatment

  42. Changes in APAP metabolism that reduce toxicity CYP2E1 CYP1A2 CYP2B GST GSH elimination ROS (Nrf-2) Regeneration Acute phase (IL-6) APAP NAPQI

  43. Transporters during recovery from APAP hepatotoxicity TNFa X X

  44. Transporters during recovery from APAP hepatotoxicity

  45. Ntcp and Mrp4 expression 48 hours after APAP Alkunes and Manatou, unpublished observations

  46. MDR1 MDR1 (P-glycoprotein) expression In submassive necrosis (human) Normal liver necrosis J Pathol 200:553, 2003

  47. MRP3 MRP3 expression in submassive necrosis (human) Normal liver necrosis J Pathol 200:553, 2003

  48. Conclusion • Adaptation to liver toxicity can involve: • a). Down regulation of CYPs and • uptake transporters • b). Upregulation of glutathione and • efflux transporters

  49. Serial ALT in healthy woman receiving APAP 1 g qid X 7 days Unpublished data

  50. Conclusions • It is adapation totoxicity. • Arguably the most important issue in idiosyncrasy. • a). Determines whether patient gets sick • b). Implications for monitoring • b). Susceptibilities may not be drug specific • Current concepts do not account for the “memory”.

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