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Drug Induced Liver Injury: Implications in drug discovery and development

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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 ... – PowerPoint PPT presentation

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Title: Drug Induced Liver Injury: Implications in drug discovery and development


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 2006 Rank Order 1
highest to 5 lowest
Overall Priority Variance Your Company's Priority Variance
Hepatotoxicity 1.1 low 1.2 low
QT Prolongation 2.6 moderate 2.5 high
Rhabdomyolosis 3.3 moderate 3.5 mod
Serious Skin Rashes SJS 3.5 high 3.4 high
Edema 4.4 high 4.5 high

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Withdrawn from the market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
Rezulin Los 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 1960s 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 lt 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 lt 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 lt 10 mg/day
  • 3). Low covalent binding in liver microsomes
  • 4). Low production of glutathione conjugates
  • 5). Low incidence (lt5) of ALT gt 3 X ULN in
    clinical trials.

16
Example Acetaminophen
1). Avoid certain molecular structures - NO 2).
Target daily dose to lt 10 mg/day 4
grams/day 3). Low covalent binding in liver
microsomes NO 4). Low production of
glutathione conjugates NO 5). Low incidence
(lt5) of ALT - NO
17
JAMA, 39287,2006
18
Example Acetaminophen
1). Avoid certain molecular structures - NO 2).
Target daily dose to lt 10 mg/day 4
grams/day 3). Low covalent binding in liver
microsomes NO 4). Low production of
glutathione conjugates NO 5). Low incidence
(lt5) 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-occlusi
ve disease Occult fibrosis/ cirrhosis Liver
cancer
Acute hepatocellular injury High ALT/AST
21
Regulatory actions due to DILI (1995-2006)
  • Second Line
  • felbamate
  • tolcapone
  • trovafloxacin

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

Withdrawals bromfenac troglitazone pemoline
Warnings acetaminophen leflunomide nefazodone
nevirapine pyrazinamide/rifampin terbin
afine valproic acid zifirlukast atomoxetine interf
eron 1b 1b and 1a saquinavir infliximab bosentan
telithromycin (kava, lipokinex)
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) - ones own, self
  • (syn) - together
  • (crasis) - a mixing, mixture
  • therefore
  • a persons 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
  • 1). Would obviate need for ALT monitoring.

2). Would be useful in developing next in
class drugs.
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
Incidence of ALT elevations (gt3X ULN) and
clinical hepatitis
hepatitis
troglitazone 2 lt0.1 INH 15 lt1
diclofenac 3 lt0.01
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. 64268 (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
Safe pathways
  • Drug

elimination
Reactive Metabolite
ALT elevations
38
jaundice
liver failure
SAFE
Increased ALT
safe
Concept of idiosyncratic hepatocellular injury
39
safe elimination
  • APAP

NAPQI
Covalent binding/oxidative stress
resolution
progression
40
Effect of 8 days APAP pretreatment (---) on
single dose toxicity in mice
Hepatology 29436, 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
  • APAP

elimination
ROS (Nrf-2)
Regeneration
Acute phase (IL-6)
NAPQI
43
Transporters during recovery from APAP
hepatotoxicity
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 200553, 2003
47
MRP3
MRP3 expression in submassive necrosis (human)
Normal liver
necrosis
J Pathol 200553, 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 to toxicity.
  • 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.

51
Where do we go from here?
  • The most appropriate model for studying
    idiosyncratic hepatotoxicity are the people who
    actually experienced this.

52
Selection of cases and controls from serial ALT
values in a clinical trial
C.V.
Non-susceptible
susceptible

ULN
53
A cooperative agreement funded by the Division
of Digestive Diseases and Nutrition, National
Institute of Diabetes and Digestive and Kidney
Diseases
http//dilin.dcri.duke.edu/
54
Sphere of Influence
12.8 million lives
http//dilin.dcri.duke.edu/
55
Resources Created by DILIN 1). Genomic DNA
bank. 2). Immortalized lymphocyte bank. 3).
Registry of subjects.
56
Final take home points
  • 1). The DILIN network represents the best
    opportunity to date to identify mechanisms
    underlying severe idiosyncratic DILI.
  • 2). Research utilizing the resulting resources
    will be challenging.

57
Idiosyncratic hepatocellular injury due to
drugs is a model for all environmental disease

1). Large population with known exposure to a
defined xenobiotic (the drug). 2). Biomarkers
that are cheap, safe, and sensitive.
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