Recognizing Drug Induced Liver Injury in Exposed Populations

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) 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 1 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. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 2 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 3 “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. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 4 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” 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 5 Drug-Induced Liver Injury (DILI) “tolerators” Time Course of Liver Tests "tolerator" - M47 - Gilbert's syndrome 100.0 ALTx start drug ASTx ALPx 10.0 TBLx stop drug Test Values, (xULN) 1.0 0.1 28 January 2005 -60 0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 Days Since Exposed to Drug FDA/CDER-AASLD-PhRMA HepTox Steering Group 6 Drug-Induced Liver Injury (DILI) “adaptors” Time Course of Liver Tests "adaptor" - M63 - transaminase rises only 100.0 ALTx start drug ASTx ALPx 10.0 TBLx stop drug Test Values, xULN 1.0 0.1 28 January 2005 -60 0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 Days Since Exposed to Drug FDA/CDER-AASLD-PhRMA HepTox Steering Group 7 Drug-Induced Liver Injury (DILI) “susceptibles” Time Course of Abnormalities Patient xxx F44, "susceptible" 2.0 100xULN start Drug stop Drug ALT AST ALP GGT 1.5 Log(10) of xULN 1.0 10xULN TBL 0.5 0.0 ULN ------------hospitalized----------------- -0.5 -1.0 0 15 30 45 60 75 90 105 Study Day 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 120 -15 8 … not DILI Time Course of Liver Tests male 72, placebo 100.0 start drug stop drug altx astx alkx bilx Test Values, xULN 10.0 2xULN 1.0 subacute hepatitis B 0.1 -60 -30 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 540 570 Study Day 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 600 9 Is It a Bad Drug or Is It a Susceptible 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? 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 10 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 FDA/CDER-AASLD-PhRMA HepTox Steering Group 11 28 January 2005 peroxisome proliferator-activated receptor- (PPAR) agents H2 C CH3 H3C HO CH3 troglitazone (REZULIN) 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 12 Relative Hepatotoxicity in Class “- glitazones” (thiazolidenediones) H2 C CH3 S N H O O O O H2 C H2 C O S N H O O - glitazone (G) - methoxy-phenyl-methyl- thiazolidinedione 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 13 The Glitazone Family CH3 H3 C O CH3 [G] CH3 N [G] HO CH3 N [G] N tro-glitazone REZULIN Sankyo 1963 pio-glitazone ACTOS Takeda 1986 rosi-glitazone AVANDIA Beecham 1989 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 14 Other Drug “Families” • “-profens” – benoxaprofen – flurbiprofen – ibuprofen • “-pidems” – alpidem – zolpidem • “-navirs” • “-fenacs” – ibufenac – bromfenac – diclofenac 28 January 2005 – – – – ritonavir indinavir nefinavir saquinavir FDA/CDER-AASLD-PhRMA HepTox Steering Group 15 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 16 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 17 " Our study is man, as the subject of accidents or diseases. Were he always, inside and outside, cast in the same mould, instead of differing from his fellow man as much in constitution and in his reaction to stimulus as in feature, we should ere this have reached some settled principles in our art. The practice of medicine is an art, based on science ... it has not reached, perhaps never will, the dignity of a complete science, with exact laws, like astronomy or engineering.” William Osler, M.D. (1849-1919) “Teacher and Student,”Minneapolis 1892 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 18 Hippocrates 460-377 B.C. The Father of Medicine " …he who aspires to treat correctly of human regimen must first acquire knowledge and discernment of the nature of man in general – knowledge of its primary constituents and discernment of the components by which it is controlled. … though they are made from the same materials, no two are alike…” 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 19 Hippocrates “Nature of Man” elements qualities fire hot water wet air cold earth dry “Airs, Waters, Places” “Epidemics” “Nutriment” 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 20 constituents blood phlegm bile - yellow bile - black Why Are They Susceptible ? “idio-sug-krasia” (Hippocrates, ~ 400 B.C.) idios () - one‟s own, self syn () - together crasis () - 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] 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 21 4*4@FL(6DVF4V (idiosugkrasia) s.f., (substantive, feminine) temperament; constitution Pocket Oxford Greek Dictionary Oxford University Press, Oxford UK, 2000 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 22 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 23 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? FDA/CDER-AASLD-PhRMA HepTox Steering Group 24 28 January 2005 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) 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 25 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? 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 26 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. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 27 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 28 Liver “Function” Tests • what are they ? • what do they mean ? Important: distinguish between liver function and liver injury • they’re the biomarkers we use 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 29 Commonly Used Tests “transaminases”: ALT enzymes injury AST alkaline phosphatase gamma-glutamyl transferase bilirubin (total, “direct”) hepatocellular cholestatic function excretory synthetic synthetic 30 substances albumin prothrombin (INR) 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 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 MAY indicate hepatocellular injury 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 31 Is Serum Transaminase Enough? Serum ALT > 3x ULN ? Yes “positive” No “negative” incidence 1 per 1000 DILI i 95 5 100 sensitivity 95% none u 999 98,901 99,900 specificity 99% totals 1,094 98,906 100,000 predictive power 8.7% 99.995% accuracy 99% 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 32 Need Very, Very Specific Tests Tyranny 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 33 Hy Zimmerman 1917-1999 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 34 ESTIMATED CASE FATALITY RATE IN DRUGINDUCED ACUTE HEPATOCELLULAR INJURY WITH NON-OBSTRUCTIVE JAUNDICE DRUG alpha-methyldopa isoniazid iproniazid phenytoin cinchophen Halothane 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group APPARENT FATALITY RATE 10% >10% 15% >40% 50% 50% Zimmerman. HEPATOTOXICITY, 1978 & 1999 35 Intrinsic vs Idiosyncratic Toxicity • “intrinsic” – – – – – – predictable dose-related similar in animals high incidence short interval types • directly destructive • indirect, metabolic • cholestatic 28 January 2005 • “idiosyncratic” – – – – – – unpredictable not dose-related not seen in animals low incidence, rare variably longer interval types • hypersensitivity • metabolic …H. Zimmerman, 1978 36 FDA/CDER-AASLD-PhRMA HepTox Steering Group 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 phosphorus amanita phalloides carbon tetrachloride anabolic steroids tetracycline chlorpromazine phenytoin penicillin Intrinsic Toxicity ------------------------------------some of both--------------------------------------- Host Susceptibility ___________________________________________________________________________________________ 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 37 “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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 38 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. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 39 “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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 40 Distribution of Peak Values placebo 2.0 Log10(xULRR) peak TBL drug xxx 3xULRR 1.5 1.0 0.5 0.0 -0.5 normal range -1.0 -1.0 -0.5 0.0 Hy's Law Gilbert's; cholestasis 2xULRR Temple's Corollary 0.5 1.0 1.5 2.0 41 Log10(xULRR) peak ALT 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 42 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 43 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 44 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 45 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 46 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 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 47 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 ? 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 48