Post on 15-Sep-2018
transcript
Yimin Mao
Renji HospitalShanghai Jiaotong University School of Medicine
The Future Outlook to DILI Research From The Perspective of China
DILI in General Population
Less than 20/100,000
The incidence increased in the elder people
Drug Can Cause All Kinds of Liver Injury We Have Ever Known
DILI is one of the most common reason for unknown cause liver injury/liver disease
DILI in Different Countries
DILI-R Research
Study Population: Hospitalized Patient during
2012-2014 303 hospitals nationwide
which cover all 31 provinces in mainland China involved
29,687 DILI cases in total enrolled
DILI Incidence Among Hospitalized Patients
DILI 3-year incidence:1.75
DILI incidence () by geographic locations of China
South SW North NW East Central NE
unpublished data
Increasing DILI Incidence
Trend of DILI Incidence () of China
2012 2013 2014
unpublished data
DILI Incidence Higher in Non-tertiary Hospitals
P < 0.001
Tertiary Non-tertiary
DILI incidence () in tertiary and non-tertiary hospitals of China
unpublished data
Top-10 Classes of Suspicious Drug in General Hospitals
Anti-biotics (include anti-TB drug) herbsChinese patent druganti-tumor drug are
major suspicious drugsunpublished data
TCM
Top-20 Suspicious Drugs
unpublished data
Compare with WM , DILI Latentperiod is longer for those who Take TCM
P < 0.001
TCM Westen Medicine
unpublished data
40% DILI Patients Take at Least 2 Suspicious Drugs
Unsure
1 suspicious drug
2 suspicious drugs
3 or more
unpublished data
Live Injury Types
Hepatocellular injury
Cholestatic injury
Mixed injury
Unsure
unpublished data
At Baseline, ALT Above 10xULN Among 30% Patients
Missing, unknown
unpublished data
30% patients meet criteria of Hy's Law
About 3% patients progressed to liver failure or death
Percentage of Hepatocyte injury type of DILI meeting Hy's Law criteria
YesNo
unpublished data
Liver Histology Presents Many Kinds of Liver Injury
Liver histology charateristics Cases and percentageAcute hepatitis 438(28.59%)Chronic hepatitis 239(15.60%)Acute cholestasis 15(0.98%)Chronic cholestasis 10(0.65%)Cholestatic hepatitis 72(4.70%)Granulomatous change 3(0.20%)Macrosteatosis 9(0.59%)Microsteatosis 10(0.65%)NASH 17(1.11%)Coagulation/fusion necrosis 3(0.20%)Non focal necrosis 1(0.07%)Hepatocyte change 44(2.87%)Mixed or miscellaneous liver injury 3(0.20%)Slight nonspecific change 57(3.72%)Absolutely normal 4(0.26%)Massive necrosis 2(0.13%)Other 392(25.59%)Unknown 219(14.30%)
Among 1532 casesChronic DILI are16.25%unpublished data
Interventional Research
Magnesium Iso-glycyrrhizinate(MgIG) in The Treatment of Subjects with DILI
Low dose 100mg/d(N=72)
High dose 200mg/d(N=72)
Tiopronin 100mg/d(N=72)
216 DILI patients
0 w 4 w
Randomized, double-blind, multi-doses, active drug controlled , multi-center study
Primary endpoint:
ALT normalization at weeks 4
Study Subjects
Rates of ALT Normalization At Weeks 1-4
unpublished data
Group A: low dose study drug;Group C: high dose study drug Group B: active control
P < 0.001 at Week 23 and 4
Rates of ALT Normalization At Weeks 1-4 for Subjects Who Stopped Suspicious Drug
unpublished data
P < 0.001 at Week 3 and 4
Chart1
0.25710.28950.2727
0.57140.50.6667
0.82860.55260.8182
0.88570.65790.8788
Group A
Group B
Group C
alt
W1W2W3W4
Group A27.12%62.71%81.36%84.75%
Group B25.42%45.76%52.54%61.02%
Group C30.36%69.64%78.57%85.71%
Group AGroup BGroup C
84.75%61.02%85.71%
Group AGroup BGroup C
W127.12%25.42%30.36%
W262.71%45.76%69.64%
W381.38%52.54%78.57%
W484.75%61.02%85.71%
Alt[2,5)
W1W2W3W4
Group A33.33%73.33%84.44%86.67%
Group B27.66%46.81%55.32%59.57%
Group C40.54%75.68%81.08%86.49%
ALT5
W1W2W3W4
Group A7.14%28.57%71.43%78.57%
Group B16.67%41.67%41.67%66.67%
Group C10.53%57.89%73.68%84.21%
[2,5]ULN>5ULN
Group A86.67%78.57%
Group B59.57%66.67%
Group C86.49%84.21%
W1W2W3W4
Group A25.71%57.14%82.86%88.57%
Group B28.95%50.00%55.26%65.79%
Group C27.27%66.67%81.82%87.88%
W1W2W3W4
Group A29.17%70.83%79.17%79.17%
Group B19.05%38.10%47.62%52.38%
Group C34.78%73.91%73.91%82.61%
alt
Group A
Group B
Group C
ast
W1W2W3W4
Group A44.83%72.41%75.86%79.31%
Group B32.00%52.00%52.00%48.00%
Group C60.71%82.14%85.71%89.29%
Group A
Group B
Group C
Group A
Group B
Group C
Group A
Group B
Group C
[2,5]ULN
>5ULN
Group A
Group B
Group C
Group A
Group B
Group C
ast
Group A
Group B
Group C
ALT
BaselineW1W2W3W4
Group A203.53103.6866.1559.553.41
Group B168.95124.6992.6180.277.06
Group C221.08103.9954.9752.6646.37
BaselineW1W2W3W4
Group A160.585444038
Group B14496.56256.955
Group C16574.85454239
ALT
Group A
Group B
Group C
AST
BaselineW1W2W3W4
Group A172.1560.1343.2240.1637.18
Group B162.2670.5356.3746.9246.45
Group C222.349.7743.1737.8235.84
Group A
Group B
Group C
AST
Group A
Group B
Group C
ALTuln
BaselineW1W2W3W4
Group A3.751.911.211.141
Group B3.242.381.861.621.55
Group C4.131.981.051.040.9
BaselineW1W2W3W4
Group A31.610.860.760.75
Group B2.761.651.160.970.92
Group C3.441.450.90.830.79
ALTuln
Group A
Group B
Group C
ASTuln
BaselineW1W2W3W4
Group A4.151.411.020.940.88
Group B4.021.721.331.131.12
Group C5.281.181.030.90.85
Group A
Group B
Group C
ASTuln
Group A
Group B
Group C
Rates of ALT Normalization At Weeks 1-4 for Subjects Who Cont' with Suspicious Drug
unpublished data
P < 0.001 at Week 23 and 4
Chart1
0.29170.19050.3478
0.70830.3810.7391
0.79170.47620.7391
0.79170.52380.8261
Group A
Group B
Group C
alt
W1W2W3W4
Group A27.12%62.71%81.36%84.75%
Group B25.42%45.76%52.54%61.02%
Group C30.36%69.64%78.57%85.71%
Group AGroup BGroup C
84.75%61.02%85.71%
Group AGroup BGroup C
W127.12%25.42%30.36%
W262.71%45.76%69.64%
W381.38%52.54%78.57%
W484.75%61.02%85.71%
Alt[2,5)
W1W2W3W4
Group A33.33%73.33%84.44%86.67%
Group B27.66%46.81%55.32%59.57%
Group C40.54%75.68%81.08%86.49%
ALT5
W1W2W3W4
Group A7.14%28.57%71.43%78.57%
Group B16.67%41.67%41.67%66.67%
Group C10.53%57.89%73.68%84.21%
[2,5]ULN>5ULN
Group A86.67%78.57%
Group B59.57%66.67%
Group C86.49%84.21%
W1W2W3W4
Group A25.71%57.14%82.86%88.57%
Group B28.95%50.00%55.26%65.79%
Group C27.27%66.67%81.82%87.88%
W1W2W3W4
Group A29.17%70.83%79.17%79.17%
Group B19.05%38.10%47.62%52.38%
Group C34.78%73.91%73.91%82.61%
alt
Group A
Group B
Group C
ast
W1W2W3W4
Group A44.83%72.41%75.86%79.31%
Group B32.00%52.00%52.00%48.00%
Group C60.71%82.14%85.71%89.29%
Group A
Group B
Group C
Group A
Group B
Group C
Group A
Group B
Group C
[2,5]ULN
>5ULN
Group A
Group B
Group C
Group A
Group B
Group C
ast
Group A
Group B
Group C
ALT
BaselineW1W2W3W4
Group A203.53103.6866.1559.553.41
Group B168.95124.6992.6180.277.06
Group C221.08103.9954.9752.6646.37
BaselineW1W2W3W4
Group A160.585444038
Group B14496.56256.955
Group C16574.85454239
ALT
Group A
Group B
Group C
AST
BaselineW1W2W3W4
Group A172.1560.1343.2240.1637.18
Group B162.2670.5356.3746.9246.45
Group C222.349.7743.1737.8235.84
Group A
Group B
Group C
AST
Group A
Group B
Group C
ALTuln
BaselineW1W2W3W4
Group A3.751.911.211.141
Group B3.242.381.861.621.55
Group C4.131.981.051.040.9
BaselineW1W2W3W4
Group A31.610.860.760.75
Group B2.761.651.160.970.92
Group C3.441.450.90.830.79
ALTuln
Group A
Group B
Group C
ASTuln
BaselineW1W2W3W4
Group A4.151.411.020.940.88
Group B4.021.721.331.131.12
Group C5.281.181.030.90.85
Group A
Group B
Group C
ASTuln
Group A
Group B
Group C
MgIG Approved of the Indication To Treat Acute DILI
The only drug approved of DILI indication globally
Translational Research Between Basic and Clinical
Pro-inflammatory cytokines (TNF, IL-1, )
Viruses, Bacteria
Inflammatory response
TLRs, TNFR, IL-1R
IG IG
IG
p38, JNK, ERKMAPK IKK
PGE, PGI,
TBX2, LTB4
COX
LOX
PLA2
Cytokines (TNF-, IL-1, IL-6)
Chemokines (IL-8)
Enzymes (iNOS, COX-2, LOX, PLA2)
AA AP-1 IB/NF- B(p65/p50)
Dose dependently inhibit 3 major Inflammatory pathway PLA2/AA signal channel
NF-B signal channel
MAPK/AP-1 signal channel
Anti-inflammation Mechanism of MgIG
25
Bicyclol, Class I new drug of China
ALT decrease in CCI4-included liver injury
Bicyclol Inhibit expression and activity of
inflammatory cytokinesNF-KB
Blank control group
Oligonucleotide group
0Oligonucleotide + bicyclol group
20
40
60
**P
RCT Study on Bicyclol to Treat DILI Has Been Initiated
Prospective Research Is Ongoing
More than 100 hospitals involved Follow up at least 6 month Collect clinical information Set up sample bank Biomarker research
A Professional DILI Platform in ChinaHepaTox
www.hepatox.org
Released The First DILI Clinical Guideline in China
The Future Outlook To DILI Translational Research
Diagnosis Confirm normal ALT Develop new method for causality assessment
Pathogenesis Idiosyncratic animal model Host ,drug and enviromental
Risk factors Host ,drug and enviromental
Biomarkers Diagnosis Tolerators, adaptors, susceptibles Prognosis
Treatment
Regional/Global cooperation is
needed
Thank you for your attention!www.hepatox.org