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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
(DILI) is Hot
FDA / Pharma steering committee
Several Critical Path Initiatives
$ millions spend in industry
New Network (DILIN)
SAE Consortium
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
Troglitazone (Rezulin®)
1). PPARg agonist
2). Treats type 2 diabetes
3). Caused liver failure
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
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 Withdrawn from the market
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.”
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% of total terminations
Why clinical drug development
programs were terminated in 1991
Nature Reviews: Drug Discovery, Aug, 2004
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% of total terminations
Why clinical drug development
programs were terminated in 2000
Nature Reviews: Drug Discovery, Aug, 2004
“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
2006 State of the Art
How to avoid hepatotoxicity in
drug development
1). Avoid certain molecular structures
Compound Pair
O
Ibuprofen
“Clean” Compound
HO
O
Ibufenac
“Toxic” Compound*
HO
*withdrawn from the market in the 1960’s because of clinical liver toxicity
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
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
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.
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
Watkins et al.
ALT vs. time for APAP Group (n = 26), ULN = 40
Solid Line = on treatment, Dotted Line = off treatment
640
16 X
APAP Mean ALT
3 X ULN R eference
14 X
480
12 X
400
10 X
320
8X
240
6X
160
4X
80
2X
0
Fold ULN for ALT
ALT
560
0X
0
5
10
15
Time (days)
20
25
30
JAMA, 392:87,2006
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
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.
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
Regulatory actions due to DILI
(1995-2006)
Withdrawals
bromfenac
troglitazone
pemoline
Second Line
felbamate
tolcapone
trovafloxacin
http://www.fda.gov/medwatch/safety.htm
Warnings
acetaminophen
leflunomide
nefazodone
nevirapine
pyrazinamide/rifampin
terbinafine
valproic acid
zifirlukast
atomoxetine
interferon 1b –1b and 1a
saquinavir
infliximab
bosentan
telithromycin
(kava, lipokinex)
Regulatory actions due to DILI
(1995-2006)
Withdrawals
bromfenac
troglitazone
pemoline
Second Line
felbamate
tolcapone
trovafloxacin
http://www.fda.gov/medwatch/safety.htm
Warnings
acetaminophen
leflunomide
nefazodone
nevirapine
pyrazinamide/rifampin
terbinafine
valproic acid
zifirlukast
atomoxetine
interferon 1b –1b and 1a
saquinavir
infliximab
bosentan
telithromycin
(kava, lipokinex)
Of the 23 drugs/CAM that
have undergone withdrawal,
restriction or warnings
19/23 (82%) were associated with acute
idiosyncratic hepatocellular injury
“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
Liver injury
( ALT)
safe
SAFE
Concept of idiosyncratic
hepatocellular injury
death
jaundice
enceph
Days on drug
Challenges in identifying
factors underlying
susceptibility to DILI
1). How to identify susceptible individuals.
2). What to do with them once you have
them.
Liver injury
( ALT)
safe
SAFE
Concept of idiosyncratic
hepatocellular injury
Selection of patients based on
serial ALT values in a clinical trial
1.34
C.V.
CV ALT
Non-susceptible
cases
0.34
susceptible
0.23
0.16
controls
0.03
0.18
0.58 0.77
1.10
34.77
ULN
Maximum ALT, fold Upper Limit of Normal (logarithmic scale)
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.
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.
Incidence of ALT elevations
(>3X ULN) and clinical hepatitis
ALT
hepatitis
troglitazone 2%
INH
15%
diclofenac
3%
<0.1
<1%
<0.01%
Treatment with tacrine
through ALT elevations
unpublished
Reversed on treatment
Treatment stopped
unpublished
Reversal of rat liver necrosis with
continued exposure to BDCM
1 week
3 weeks
Toxicol. Sci. 64:268 (2001)
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).
Safe pathways
Drug
elimination
Reactive
Metabolite
X
ALT elevations
Adaptation
Progressive injury
jaundice
liver failure
Increased ALT
safe
SAFE
Concept of idiosyncratic hepatocellular injury
safe
elimination
APAP
NAPQI
Covalent binding/oxidative stress
resolution
progression
Effect of 8 days APAP pretreatment (---)
on single dose toxicity in mice
Hepatology 29:436, 1999.
3-Cys-APAP adducts (brown) 2 hours
after single toxic APAP dose
Saline pretreatment
APAP pretreatment
Changes in APAP metabolism
that reduce toxicity
APAP
elimination
CYP2E1
CYP1A2
CYP2B
ROS (Nrf-2)
Regeneration
Acute phase (IL-6)
NAPQI
GST
GSH
Transporters during recovery
from APAP hepatotoxicity
TNFa
X
X
Transporters during recovery from APAP
hepatotoxicity
Ntcp and Mrp4 expression
48 hours after APAP
Alkunes and Manatou, unpublished observations
MDR1 (P-glycoprotein) expression
MDR1
In submassive necrosis (human)
Normal liver
necrosis
J Pathol 200:553, 2003
MRP3 expression in
submassive necrosis (human)
Normal liver
MRP3
necrosis
J Pathol 200:553, 2003
Conclusion
Adaptation to liver toxicity can involve:
a). Down regulation of CYPs and
uptake transporters
b). Upregulation of glutathione and
efflux transporters
140
120
100
80
1st study
1st study
2nd study
Day
ffool
llloow
w-uupp
1133
1
1
9
7
5
3
60
40
20
0
1
ALT (U/L)
Serial ALT in healthy woman
receiving APAP 1 g qid X 7 days
Unpublished data
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”.
Where do we go from
here?
The most appropriate model for studying
idiosyncratic hepatotoxicity are the people
who actually experienced this.
Selection of cases and controls from
serial ALT values in a clinical trial
1.34
C.V.
CV ALT
Non-susceptible
cases
0.34
susceptible
0.23
0.16
controls
0.03
0.18
0.58 0.77
1.10
34.77
ULN
Maximum ALT, fold Upper Limit of Normal (logarithmic scale)
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/
Sphere of Influence
12.8 million lives
http://dilin.dcri.duke.edu/
Resources Created by DILIN
1). Genomic DNA bank.
2). Immortalized lymphocyte bank.
3). Registry of subjects.
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.
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.