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Patient Safety: Proactive Management and Detection of Hepatotoxicity in Prevention of Drug Induced Liver Injury Andrew Botham, PhD, Head of R&D ACM Global Central Laboratory
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Patient Safety: Proactive Management and Detection of Hepatotoxicity in Prevention of Drug Induced Liver Injury Andrew Botham, PhD, Head of R&D ACM Global Central Laboratory


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Overview …

In many clinical trial scenarios, there may only be one chance to collect, ship, test and analyze a patient's specimen. These often time-sensitive snapshots into a patient's progression in a study are critical not only to the overall study results, but ultimately the safety of patients undergoing treatment.

The lifecycle of a specimen, which starts at collection and ends at database lock, can be prone to human error along each step of the testing process, particularly when conducting global clinical trials in more remote ends of the world. Sponsors need to ensure the integrity of the specimen throughout this process, while balancing the relative cost of logistics.

Based on lessons learned from managing global clinical trials testing, ACM Global Lab and its partners will share their insights on monitoring and oversight on patient safety, safeguarding sample integrity, and good business sense.

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  • 1. 1
  • 2. Background• DILI has been the single most frequent cause of safety related drug marketing withdrawals for more than 50 years.• Hepatotoxicity discovered after approval for marketing has also limited the usage of other drugs. 2
  • 3. C ontext• Severe DILI in phase 3 trials is rare.• An increased incidence of mild hepatotoxicity reflects: A potential for A capacity for only OR severe DILI. limited injury.• Essential to detect any cases of severe injury and examine each case closely. 3
  • 4. D rug Induced Liver Injury• Tolerators Most people exposed to a new drug show no injury.• Adaptors Some people show transient injury, but adapt.• Susceptibles A few fail to adapt and show serious toxicity. BAD SUSCEPTIBLE DRUG PATIENT 4
  • 5. D rug Induced Liver Injurymolecular variation in drug class differing potencies of variantstherapeutic index variations variable PK ADME among patientsvariable PD responses in patients a single dosing schedule may not suit all 5
  • 6. D rug Induced Liver InjuryA drug tolerated by all but a very few cannot be considered toxic 6
  • 7. D ILI cont’d• If you don’t look for it, you won’t find it.• Is there Injury or is there disease?• How is it?... serious?... progressive?• Is it DILI or something else? 7
  • 8. O ther C auses• Mainly acute hepatitis: viral A or B, seldom C.• Alcoholic.• Biliary stones.• Ischaemia.• Autoimmune.• Other… 8
  • 9. Bad drug vs susceptible patient• Humans are very different to animal models.• Genetically diverse.• Resistant to standardisation or pigeon-holing.• Human’s take a LOT of drugs!• Human’s have a LOT of diseases.• The ones treated are not the same as the ones studied.• They don’t always report outcomes promptly.• “…. though they are made from the same materials, no two are like…” Hippocrates 460-377 BC. 9
  • 10. Research Required• Which cytochrome isoforms interact with which parts of the molecules?• What are the toxic metabolites?• Are therapeutic and toxic parts of the molecule the same.• Further rules predicting DILI.• Humans and Animals. 10
  • 11. Mechanisms of D ILI• Drugs cause liver injuries by numerous mechanisms. Mimicking all known liver diseases.• When DILI is suspected, gather information.• In many cases, there is a delay between initiation of treatment and onset of liver injury.• In general, early trials should involve LFTs every 2-4 weeks for at least a few months.• For shorter trials post-treatment LFTs should be performed. 11
  • 12. Mechanisms cont’d• For the most part, the first evidence of a problem is discovery of elevated AT or ALP during routine measurements.• If there is no sign of liver injury after a reasonable period of exposure, the monitoring interval can increase.• However, if clinical symptoms of DILI are noted LFTs should be performed immediately. 12
  • 13. C onfirmation• An increase in AT of >3X ULN, repeat test within 48 to 72 hours for ALL LFTs. Assess symptoms.• For distanced trials, local retesting may be necessary.• If symptoms persist, or repeat testing shows AT of >3X ULN.• CLOSE OBSERVATION or DISCONTINUE DRUG 13
  • 14. Signals of D ILI; H y’s Law• Hepatocellular injury can be caused by drugs that rarely cause severe DILI (Aspirin, tacrine, statins, and heparin) as well as those who do.• Hepatocellular injury is a necessary but not sufficient signal for DILI.• The frequency of AT elevations also not useful.• Very high levels of ATs may be a better indicator of the potential for severe DILI• The most specific indicator is evidence of altered liver function. 14
  • 15. Signals Injury transaminases: ALT Hepatocellularenzymes AST akaline phosphatase Cholestatic gamma-gutamyl transferase Function bilirubin (total, direct) excretorymarkers albumin synthetic prothrombin (INR) synthetic 15
  • 16. Interpretation of Signals• The presence of just one case of severe liver injury in a premarketing DB signals high hepatotoxic risk.• There may no identifable cases, but varying degrees of serum AT abnormalities requiring interpretation.• Slight abnormalities (<3XULN) are common in untreated and placebo-treated subjects, so not useful in assessing DILI.• Greater deviations are observed >3X or 5X or 10X ULN. 16
  • 17. Interpretation cont’d• A significantly increase incidence of AT abnormalities >3X ULN is a signal of potential severe DILI.• High sensitive but not specific.• AT is not regulated by the liver. AT are found in skeletal and heart muscle, gut, etc.• For low prevalence/incidence events need extremely high specificity to avoid “finding” many false positive.• Almost impossible to find hyper-specific test. Compound test may be more effective. 17
  • 18. Interpretation cont’dSerum ALT DILI none Predictive >3X ULN i u totals Power Yes 95 999 1,094 8.7%“positive” No 5 98,901 98,906 99.995%“negative”Incidence 100 99,900 100,0001 per 1000 sensitivity specificity accuracy 95% 99% 99% 18
  • 19. H y’s Law• The causes hepatocellular injury, generally shown by a higher incidence of 3-fold of greater elevations of ALT or AST ULN than the control.• Among trial subjects showing such AT elevations, one or more also show elevation of TBIL to 2XULN, without cholestatis.• No other reason can be found to explain the combination of increase AT and TBIL (such as viral hepatitis, pre- existing acute liver disease. Hy Zimmermann 1917-1999 19
  • 20. H y’s LawIf both hepatocellular injury and jaundice occur, expect at least 10% mortality rate! Hy Zimmermann 1917-1999 20
  • 21. C ombined Elevations• Experience shows that occurrence of even one or two well documented cases in ominous.• Absence of Hy’s Law cases allows the Rule of 3 binominal assessment of the rate of severe DILI• Eg. no case in 3,000, 95% confidence that true rate ≤ 1 in 1,000. Hy’s Law assumes 10%. So, suspected severe injury rate is therefore ≤ 1 in 10,000 ?!? sorry! 21
  • 22. N ew D rug Submission (FDA experience)• Incidence of pooled data should include: – 3X, 5X, 10X, and 20X ULN elevations of AST, ALT. – Any elevations of bilirubin >2X ULN. – Any elevations in ALP of >1.5X ULN. – Elevation of AT accompanied by elevated bilirubin. – Elevation of AT accompanied by clinical symptoms e.g. nausea, vomiting, anorexia, abdominal pain, or fatigue. – Possible liver related deaths or treatment discontinuations. 22
  • 23. C RO s and C entral Labs• Assess risk of DILI. • We can interpret safety data. • We can generate the data. • We can perform the testing. • Sample integrity.  23
  • 24. Preanalytical C onsiderationsHandling Shipping Draw tube/volume Incorrectly centrifuged Haemolysis EDTA contamination Sample Stability 24
  • 25. Q uestions? T hank youDr. Andrew BothamHead of R&DACM Global Central 25