1. Drug Induced Liver Injury
Mary Ross Southworth, PharmD
Division of Cardiovascular and Renal Products
Office of New Drugs
Center for Drug Evaluation and Research (CDER)

2. Why should we care about DILI?
May cause serious or fatal liver injury
Affects drug development
Slow development
Prevent approval
Market withdrawal
Identifying susceptible patients may mitigate risk

3. What does the liver do?
Serves as the body’s chemical engineering and control center
Regulates the metabolism of internal compounds
Processes compounds from external sources (drugs)
Adaptable
Can regrow even if 2/3 resected
Regenerates rapidly if cells killed/removed
Enzyme and transporter function can be altered

4. The Liver: Many “Assaults”

5. The Liver: Many “Responses”

6. Common Causes of Acute Liver Failure
Approved Drugs
OTC Products (APAP)
Alcohol

8. Drug Induced Liver Injury (DILI): Background
Frequent cause of safety-related drug WITHDRAWALS or FAILURE TO APPROVE
Bromfenac
Troglitazone
Ximelagatran
Labeled WARNINGS
Felbamate
Isoniazid
SPECIAL USE
Bosentan
Tolcapone

9. DILI: Background Drug Hepatotoxins usually cause hepatocellular injury
Leakage of aminotransferase enzymes (AST/ALT) from injured liver
No evidence of obstruction
Drugs can also cause cholestasis
Usually reversible
Less morbid

10. DILI: Background
Cases of severe DILI may not show up in the clinical drug development program
Preclinical testing IDs overt hepatoxins
Hepatotoxicity “rare”: ≤1 per 10,000 subjects
Small numbers of patients studied, short duration
What you may see: mild liver injuries
…but enzyme signals ≠ certain severe DILI

11. Severe DILI
The ability to cause some hepatic injury is not a reliable predictor of potential for severe DILI
Severe DILI=liver function affected
NOT AST/ALT
Bilirubin, PT
Reaction often idiosyncratic
Genetic factors?
Metabolic factors?
Concomitant diseases/drugs
Nutritional status
Alcohol use
People are different (“tolerators”, “adaptors”, “susceptibles”)
No predictive biomarker identified yet

12. Assessing signals of DILI in clinical trials
Higher rate of enzyme elevation in drug vs. control group
NOT specific, but still a signal
Higher rate of marked enzyme elevations (>10x ULN; >1,000 U/L)
More specific
Hy’s Law case
Most specific
“Drug induced hepatocellular jaundice”
10 to 50% mortality from ALF

13. Hy’s law: 3 Components
Drug causes hepatocellular injury (↑ enzyme drug>control)
Among those with enzyme elevations >3x ULN, some with ↑ serum total bilirubin >2x ULN, with no cholestasis (↔ alk phos)
No other reason can be found to explain the combination
Requires clinical adjudication to determine probable cause of liver dysfunction!

14. Detection and Clinical Evaluation of suspected DILI
Frequent monitoring in early clinical studies
Symptoms may precede lab evidence!
Confirmation/characterization
Follow up testing in hours; repeat liberally, as needed
Obtain detailed history of symptoms
Obtain complete medical and medication history
Don’t forget ETOH, OTC and herbals!
GI consult as needed

15. Clinical Management of suspected DILI
Drug discontinuation
Automatically stopping drug with >3xULN increase may be unnecessary
Liver can adapt and become tolerant
Close observation warranted
Prevent progression to functional impairment
Generally, d/c drug if:
ALT/AST > 8x ULN
ALT/AST > 5x ULN for more than 2 weeks
ALT/AST >3x ULN and (total bili >2x ULN or INR > 1.5)
ALT/AST >3x ULN with symptoms

16. Clinical Management of suspected DILI
Follow-up
Follow until enzymes return to normal or baseline
Symptoms and enzymes may progress even after discontinuation
Bilirubin elevations usually follow enzyme elevations by days to weeks
Rechallenge
Can be considered
Not for patients with significant ↑ enzymes (> 5x ULN)
Not for patients with accompanying signs of an immunologic reaction

17. Gather more information to assess causality
Evaluate alternative causes
Acute viral hepatitis
Alcoholic and autoimmune hepatitis
Biliary tract disorders
Cardiovascular causes
Other uncommon causes
Drug/Exposure history
Dietary supplements, occupational exposure to toxic agents
Remember the 3rd component of Hy’s law: No other reason found for hepatotoxicity

18. Reporting DILI events to FDA
Report potential Hy’s law cases promptly
Narrative summary of the event
Include dates/times of symptoms, drug exposure
Test results (include time course, normal ranges)\
Treatment provided
Dechallenge/rechallenge
Clinical assessment
External expert consultants

19. DILI Risk: Questions with Regulatory Impact
Does the drug cause clinically significant DILI in the target treatment population?
What is the clinical signature of injury associated with the drug?
What are the ranges of doses & duration are associated with increased risk?
What are the critical patients susceptibility factors?
What incidences of mild & severe liver injury can be predicted in large treatment population?

20. Take-away points for Investigators
Individual susceptibility factors determine patient reaction
No predictive markers validated
Liver enzymes may indicate signal for risk
But they do not measure liver function (bili; INR)
Presence of one Hy’s law case is concerning
Not just lab values

21. Take-away points for investigators
Handling enzyme elevations in clinical trials
Sponsor should make sure investigators know what to do
Confirm abnormality promptly
Interrupt drug, if appropriate
Close observation and documentation
Investigate for probably cause
Rule out viral/autoimmune hepatitis; alcohol; drugs
Consult experts
Follow course until resolution, record and report findings

22. Resources
Guidance for Industry-Drug-Induced Liver Injury: Premarketing Clinical Evaluation
Livertox
Drug Induced Liver Injury Network