recognizing drug-induced liver injury (dili) in exposed populations

28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group

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Recognizing Drug-Induced Liver Injury (DILI) in Exposed Populations

John R. Senior, M.D.Associate Director for Science

Office of Pharmacoepidemiology and Statistical Science

Food and Drug Administration (FDA)


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Material presented here is based on the observations of the speaker for 20 years in academic hepatology and gastroenterology, 5 years as a senior executive in the pharmaceutical industry, 11 years in private consulting to industry, and upon 9.5 years at the FDA: 4.5 years as a medical reviewer for new gastrointestinal drugs, 3 as the Senior Scientific Advisor for hepatology in the Office of Drug Safety, 2 years as Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science. Comments made here do not reflect official policies or positions of the Agency, but are personal opinions of the presenter based on his diverse experiences mentioned.


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First, Detect it !– (if you don’t ask or look, you won’t get or find)

• Ask: Is there liver injury or disease?–serum transaminases, other enzymes, bilirubin, INR

• Is it progressive or serious?–progressive = getting worse or likely to do so–serious = disabling, life-threatening, fatal

• Drug-induced or some other cause?– no pathognomonic test for DILI, including biopsy– DILI may mimic any known liver disease


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“some other causes”

• What are they?– mainly acute hepatitis : viral A or B, seldom C,

alcoholic, biliary stones, ischemic, or autoimmune; other causes rarer

• How can they be ruled out?– what information should be collected?

• What are the odds of other causes?– It’s really a problem of differential diagnosis.


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Drug-Induced Liver Injury (DILI)

Most people exposed to a new drug show no injury;

“tolerators”

Some people show transient injury, but adapt;

“adaptors”

A few fail to adapt and show serious toxicity !

“susceptibles”


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“tolerators”

Time Course of Liver Tests"tolerator" - M47 - Gilbert's syndrome

0.1

1.0

10.0

100.0

-60 0 60

120

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1980

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Days Since Exposed to Drug

Test

Valu

es,

(xU

LN

) ALTx

ASTx

ALPx

TBLx

start drug stop drug


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“adaptors”

Time Course of Liver Tests"adaptor" - M63 - transaminase rises only

0.1

1.0

10.0

100.0

-60 0 60

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Days Since Exposed to Drug

Test

Valu

es,

xU

LN

ALTx

ASTx

ALPx

TBLx



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“susceptibles”

Time Course of AbnormalitiesPatient xxx F44, "susceptible"

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

-15 0

15

30

45

60

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90

10

5

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0

Study Day

Lo

g(1

0) o

f xU

LN

ALT

AST

ALP

GGT

TBL

start Drug stop Drug

------------hospitalized-----------------

ULN

10xULN

100xULN


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… not DILI

Time Course of Liver Testsmale 72, placebo

0.1

1.0

10.0

100.0

-60

-30 0 30 60 90 120

150

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Study Day

Te

st V

alu

es,

xU

LN

altx

astx

alkx

bilx


subacute hepatitis B

2xULN


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Is It a Bad Drug or Is It aSusceptible Patient?

• Why do a few people not tolerate it?

• What’s different about them?

• Can we find out?

• A drug tolerated by nearly everybody except a very few cannot be considered “toxic.”

• And not give them this drug?


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Given: Some Drugs are More Toxic

• many or most eliminated in development

• molecular variations in class

• differing potencies of variants

• therapeutic index varies

• variable PK ADME among patients

• variable PD responses in patients

• one dose may (will) not suit all patients


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Relative Hepatotoxicity in Class“- glitazones” (thiazolidenediones)

peroxisome proliferator-activated receptor- (PPAR) agents

OCH2

CH2

S

NH

OO

CH3

CH3

OH

CH3

O

CH3

troglitazone (REZULIN)


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OCH2

CH2

S

NH

OO

- glitazone (G)

- methoxy-phenyl-methyl- thiazolidinedione


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The Glitazone Family

O

CH3

CH3

CH3

OH

CH3

N[G] N

N

CH3

[G][G]

tro-glitazoneREZULINSankyo 1963

pio-glitazoneACTOS

Takeda 1986

rosi-glitazoneAVANDIA

Beecham 1989


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Other Drug “Families”

• “-profens”– benoxaprofen

– flurbiprofen

– ibuprofen

• “-fenacs”– ibufenac

– bromfenac

– diclofenac

• “-pidems”– alpidem

– zolpidem

• “-navirs”– ritonavir

– indinavir

– nefinavir

– saquinavir


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Need research on . . .1) which cytochrome isoforms attack what part of the molecules?

2) which metabolites are more toxic?

3) proof that efficacy and toxicity are in different parts of same molecule ?

4) some rules to predict DILI

5) mechanisms causing the DILI

6) not just in animals, but in humans


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Should We Be Looking More Carefully at the Patients ?

• Humans are often very different than animal models• They are incredibly diverse genetically• They resist being standardized or controlled• They take a lot of drugs, diets, supplements, alcohol• They have lots of other diseases/disorders/activities• The ones treated are not the same as the ones studied• They don’t always report troubles promptly


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"" Our study is man, as the subject of accidents or Our study is man, as the subject of accidents or diseases. Were he always, inside and outside, cast diseases. Were he always, inside and outside, cast in the same mould, instead of differing from his in the same mould, instead of differing from his fellow man as much in constitution and in his fellow man as much in constitution and in his reaction to stimulus as in feature, we should ere reaction to stimulus as in feature, we should ere this have reached some settled principles in our art. this have reached some settled principles in our art. The practice of medicine is an art, based on The practice of medicine is an art, based on science ... it has not reached, perhaps never will, science ... it has not reached, perhaps never will, the dignity of a complete science, with exact laws, the dignity of a complete science, with exact laws, like astronomy or engineering.”like astronomy or engineering.”

William Osler, M.D. (1849-1919)William Osler, M.D. (1849-1919)““Teacher and Student,”Minneapolis 1892Teacher and Student,”Minneapolis 1892


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"" …he who aspires to treat correctly of …he who aspires to treat correctly of human regimen must first acquire human regimen must first acquire knowledge and discernment of the knowledge and discernment of the nature of man in general nature of man in general –– knowledge knowledge of its primary constituents and of its primary constituents and discernment of the components by discernment of the components by which it is controlled.which it is controlled.… … though they are made from the though they are made from the same materials, no two are alike…”same materials, no two are alike…”

Hippocrates 460-377 B.C.Hippocrates 460-377 B.C.

The Father of MedicineThe Father of Medicine


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HippocratesHippocrates ““Nature of Man”Nature of Man” elementselements qualities qualities constituents constituents

firefire hot hot blood bloodwaterwater wet wet phlegm phlegmairair cold cold bile - yellow bile - yellowearthearth dry dry bile - black bile - black

““Airs, Waters, Places”Airs, Waters, Places” “ “Epidemics”Epidemics”

“ “Nutriment”Nutriment”


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Why Are They Susceptible ?“idio-sug-krasia” (Hippocrates, ~ 400 B.C.)

idios () - one’s own, selfsyn () - togethercrasis () - mixing, mixture

therefore, a person’s own individual mixture of characteristics, factors; “nature and nurture,” unique in the world

[it does NOT mean rare, unexpected, unexplained, although it may or may not be any or all of them]


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(idiosugkrasia)(idiosugkrasia) s.f., (substantive, feminine) s.f., (substantive, feminine)

temperament; constitutiontemperament; constitution

Pocket Oxford Greek DictionaryPocket Oxford Greek DictionaryOxford University Press, Oxford UK, 2000Oxford University Press, Oxford UK, 2000


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Factors in Idiosyncrasy

• genetic, bestowed at conception–gender–cytochromes, enzymes, transport systems

• acquired in life since conception–age, activities, travels–infections, immunities, diseases–diet, obesity, dietary supplements–other drugs, chemical exposures


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Especially Susceptible Patients

• adverse effect, often not dose-related• may not be duration-related• may not depend on prior disease• unexpected, unpredictable (up to now)• risk factors not well known• toxicity often uncommon or rare• who are they? how can they be identified?


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Drug Development Issues: Idiosyncratic Drug Toxicity

• Occurs despite careful preclinical testing in animals• … and despite careful and costly clinical trials• Some problem (perhaps wrong) assumptions:

– Assuming drug variability is the key to safety

– Obsolete concepts of “safe and effective” – for all?

– Assuming one dose/regimen suits all patients

– Focus on efficacy, little on safety (especially if rare)


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Needles in the Haystack Tyranny of the Numbers - I

• if only 1 patient in 1000 reacts adversely to a drug, should we call the drug “toxic”?

• If 1 person in 1000 is idiosyncratically hyper-susceptible to show drug-induced liver injury, how many patients need to be observed to have 95% chance of finding at least 1?


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A Binomial Answer . . .- if i = incidence of a rare event, and u = usual absence of the event, then (i + u) = 1, it happens or it doesn’t. And (i + u)N, where N = number of persons

- when uN, the chance of seeing no events in a group of N persons, is <0.05, then the chance of seeing at least one is >95%, because 1 – uN = 1- <0.05 = >95%

- for (0.001 + 0.999)N, need 2995 people to make (0.999)2995 = 0.04996, which is <0.05;

- in general, N 3/i for rare events.


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Detection of Rare Safety Problems

• Before approval and marketing– NDA review: seldom have enough patients, so

rare but serious event may not be observed; but if they are seen, investigate!

• After marketing and clinical use– spontaneous, voluntary reporting useful, but

severely underreported and incomplete data– problems usually worse after marketing


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Liver “Function” Tests• what are they ?• what do they mean ?Important: distinguish between liver

function and liver injury

• they’re the biomarkers we use


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Commonly Used Tests

enzymes

“transaminases”: ALT

AST

alkaline phosphatase

gamma-glutamyl transferase

substances

bilirubin (total, “direct”)

albumin

prothrombin (INR)

injury

hepatocellular

cholestatic

function

excretory

synthetic

synthetic


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Is Serum ALT a Liver Function Test ?

• serum enzymes not just from liver but also from skeletal and heart muscle, gut, etc.

• . . . so let’s not assume “liver”

• it is not a function or job of the liver to regulate the level of serum enzyme activity

• . . . so let’s not say “function”

• elevated serum ALT activity MAYMAY indicate hepatocellular injury


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Is Serum Transaminase Enough?

Serum ALT > 3x ULN ?

DILI i

none u

totals

predictive power

Yes “positive”

95

999

1,094

8.7%

No “negative”

5

98,901

98,906

99.995%

incidence 1 per 1000

100

99,900

100,000

sensitivity 95%

specificity 99%

accuracy 99%


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Need Very, Very Specific TestsTyranny of the Numbers - II

• For relatively low prevalence or incidence events, need extremely high specificity of test to avoid “finding” many false positives

• Almost impossible to find a hyper-specific test; compound tests may help: ALT+TBL

• Probably need to add clinical differential diagnostic data and methods to attain


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Hy Zimmerman

1917-1999


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ESTIMATED CASE FATALITY RATE IN DRUG-INDUCED ACUTE HEPATOCELLULAR INJURY

WITH NON-OBSTRUCTIVE JAUNDICE

DRUG APPARENT FATALITY RATE

alpha-methyldopa 10%

isoniazid >10%

iproniazid 15%

phenytoin >40%

cinchophen 50%

Halothane 50%

Zimmerman. HEPATOTOXICITY, 1978 & 1999


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Intrinsic vs Idiosyncratic Toxicity

• “intrinsic”– predictable– dose-related– similar in animals– high incidence– short interval– types

• directly destructive• indirect, metabolic• cholestatic

• “idiosyncratic”– unpredictable– not dose-related – not seen in animals– low incidence, rare– variably longer interval– types

• hypersensitivity• metabolic

…H. Zimmerman, 1978


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HZ…but that’s an oversimplification!“…this dichotomy into intrinsic toxicity or host idiosyncracy is an overly simplified formulation. The potential for injury is arranged along a spectrum, … modified by several different mechanisms.”

Relative Importance for Hepatotoxicity

phosphorusamanita phalloides

carbon tetrachloride anabolic steroidstetracycline

chlorpromazinephenytoin

penicillin

Intrinsic Toxicity ------------------------------------some of both--------------------------------------- Host Susceptibility___________________________________________________________________________________________


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“Hy’s Law” ...for drug-induced hepatotoxicity

• If both hepatocellular injury and jaundice occur, look out for at least 10% mortality!

• i.e., when both transaminase and bilirubin elevations occur together.

Robert Temple, FDA, 1999


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Searching for Clues, Predictors• Can ways be found to search pre-approval

clinical databases (NDA submissions) for clues or “signals” that predict liver failure in at least some who show the signal?

• Hy Zimmerman was on to a key concept - the combination of an indicator of injury and loss of overall function may be a valid predictor. It needs confirmation.


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“Temple’s Corollary” ...for drug-induced hepatotoxicity:

Hy’s Law cases arise out of a background of increased incidence of transaminase elevations

• Hy’s Rule-type serious cases of DILI usually arise from a background of increased injury rates, so

• Look for more ALT elevations in those exposed to drug, compared to placebo or control drug.

Robert Temple, FDA, 2004


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Distribution of Peak Values

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0-1

.0

-0.5 0.0

0.5

1.0

1.5

2.0

Log10(xULRR) peak ALT

Lo

g10

(xU

LR

R)

pea

k T

BL

placebo drug xxx

normal range Temple's Corollary

Hy's Law

Gilbert's;cholestasis

2xULRR

3xU

LRR


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What to Do When a “Signal” Detected

“signal” = laboratory abnormality, complaint, finding

• immediately (within day or two) confirm by repeat tests, examination, questions

• investigate possible causes AT ONCE ! r/o disease• start close observation (3x/week) immediately• obtain more information about possible causes• obtain consultation as appropriate or needed• follow closely (weekly, prn) to normalization or

worsening and management decision


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It may be DILI if it’s nothing else

• Diagnosis of exclusion; no test FOR DILI• Must gather data to rule out other causes• Need to educate “docs” to do it better• Develop model for quantitative likelihood estimate• Prospective large safety studies needed:

• for true incidence• for risk factors and to design risk management plans• for ‘omic’ analyses (gen-, prote-, metabon-) specimens

for elucidation of mechanisms


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Tip of the Iceberg

Death or Tx

Acute Liver Failure

Serious DILI – Threatening

Detectable DILI – but Not Serious

Patient Adaptation to New Agent Exposure

Patients/People Tolerate Exposure Without Effects


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Serious Adverse Events

• Often have relatively low incidence rate, i

• Difficult to establish correct value for i

• Voluntary reporting gives uncertain values

• May be missed in the usual efficacy trials

• Must balance modest clinical benefits for many against serious risks for a few

• Spontaneous reports (AERS) not enough


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Retrospective Database Studies

• Epidemiologic, observational – closer to reality

• A definite improvement on spontaneous reports

• Limited to who was included, data recorded

• No attribution of causality; statistical differences

• Can improve estimates of incidence, risk factors

• But cannot investigate mechanisms or causes or “do it right” in real time, collect specimens


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How many patients to study?

• Prospective, not retrospective

• Focus on safety, as drug actually prescribed

• Large and long enough to find rare events

• Full accounting, numbers of cases/exposed

• Use patient self-reporting, then investigate possible cases intensely; get needed info

• Prospective case-control design

• Impartial study conduct: NIH or AHRQ


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Prospective Large Safety Studies

• Offer best chance to learn, and to protect patients• Need to establish true incidence of DILI• Need to identify risk factors for rational RM• Need to investigate mechanisms• In best interests of everybody, including patients,

regulators, and sponsors• In 2005, are we content with safety meaning

“not poison,” and withdrawing “toxic” drugs ?

recognizing drug-induced liver injury (dili) in exposed populations

Documents

new drug

transient injury

fatal drug

office of drug safety

biopsy dili

associate director

senior executive

exposed populationsjohn