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)

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 www.fda.gov

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

The Liver: Many “Assaults”

The Liver: Many “Responses”

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

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

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

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

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

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

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!

Detection and Clinical Evaluation of suspected DILI Frequent monitoring in early clinical studies Symptoms may precede lab evidence! Confirmation/characterization Follow up testing in 48-72 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

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

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

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

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

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?

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

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

Resources Guidance for Industry-Drug-Induced Liver Injury: Premarketing Clinical Evaluation http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf Livertox https://livertox.nih.gov/ Drug Induced Liver Injury Network http://www.dilin.org/