Download Sharing Information, asking questions – liver safety data warehouse?

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Reasons why drugs are withdrawn from the market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