Clinical Assessment of Liver Toxicity Due to Telithromycin (Ketek

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Clinical Assessment of Liver Toxicity Due to
Telithromycin (Ketek)

• William M. Lee, MD
• Professor of Internal Medicine
• UT Southwestern Medical Center
• Dallas, TX
• www.acuteliverfailure.org
• December 14, 2006

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William M. Lee, MDUT Southwestern Medical Center
at Dallas

• I have no financial relationship(s) to disclose
  within the past 12 months relevant to my
  presentation.
• AND
• My presentation does not include discussion of
  off-label or investigational use.

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Assessment of Liver Safety/ToxicityGoals of this
discussion/context

• Review post-marketing data regarding drug
  hepatotoxicity related to Ketek
• After the Annals of Internal Medicine article, we
  began to review cases with FDA group Seeff,
  Avigan, Serrano, Brinker, Lee, beginning June
  2006
• We have now adjudicated 112 cases, held detailed
  discussion of 53 cases reported here

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Ketek review groupFormat of meetings

• 6 meetings over the past 5 months, 2 hours each
• Individual review of AERS/Medwatch/DILIN docs
• Discussion of each of the 53 cases on the telecon
• Developed an opinion, not a consensus
• All opinions were within one grade of probability
• Used DILIN system for severity and likelihood

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Insufficient data
Very likely
Probable
Possible
Unlikely
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Ketek review group II

• 113 cases reviewed 60 discarded as having
  another obvious cause, insufficient data or minor
  abnormality
• 53 cases subject of this further analysis
• Pattern of cases has emerged, helped by seeing
  all cases side by side

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Ketek Pattern of toxicityUnique features

• Very rapid onset
• Prominent fever, joint aches, RUQ pain
• Variable resolution quick, sub-acute, chronic
• Unusual features in some cases
• Ascites
• Rhabdomyolysis
• Eosinophilia

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28 very likely/probable, an additional 17
possible, 8 insufficient data
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Ketek Pattern of toxicity7/53 cases died or
transplanted

• 5 deaths, 2 transplants
• 1 very likely, 1 probable, 4 possible, 1 inad
  info
• Mean age 59 (range 26-85) 5F/2M
• 3/7 with ascites not counting perit dialysis pt
• 2 with fever, 3 with abdominal pain
• Mean AST 2288 IU/L
• Mean latency 5 days, exc for one 4 wks

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Ketek Pattern of toxicity contd. 7/53
death/transplant cases

• Acetaminophen yes in 2/7, ? amounts
• Biopsy/explant/autopsy 2 massive necrosis, 1
  cirrhosis but after 6 wks
• Most had viral serologies and imaging

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Ketek Overall data 53 cases

• Many hospitalized cases were quite severe
• Mean latency 23.5 days (range 1-39 days)
• Mean AST 1051
• 8 with increased Cr levels
• 9 with INR 1.5
• Biopsy/explant/autopsy N9
• Most showed changes compatible with drug-induced
  hepatitis, massive necrosis

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Ketek Pattern of toxicityTypical severe case

• 80 yr old male, given Ketek for bronchitis
• 3 days later admitted with persistent bronchitis
• Over the next 5 days, develops progressive liver
  failure and dies on 6th hospital day, few labs
  available
• No significant past med hx, no drugs, no viruses

Prob 2/Severity 4
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Ketek Pattern of toxicityAnother severe case 5

• 85 yr old woman, given Ketek for 7 days for CAP
• Admitted on day 8, weak, to ICU
• Following day AST/ALT 5525/3870 inc troponin
• Blood cultures negative
• Succumbs to liver failure, ? which day
• No confounding issues

Prob 3/Severity 4
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Ketek Pattern of toxicityMilder case 16

• 31 yr old health care executive
• URI led to two courses of Ketek, back to back
• On day 15, developed high fever, shaking chills,
  no RUQ pain. All imaging and serologies negative
• AST 583/ALT 1091, no signif bilirubin elevation
• It is highly probable that this is..drug induced
  liver injury due to this antibiotic.

Prob 4/Severity 3
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Ketek Pattern of toxicityMilder case 15

• 27 yr old male took Ketek for 5 days, no other
  meds
• 1 day after completion, developed dark urine
• T Bili 8.7 AST 227/ALT272 Alk phos 413 INR 0.9
• All viruses negative
• Physician said there is no alternative
  explanation of this event.

Prob 4/Severity 3
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Ketek Pattern of toxicityAscites case 24

• 22 yr old female took Ketek for one course, at
  day 12 began another course. At day 14, N/V,
  abdominal pain and fever pale and weak. No
  other PHI.
• T Bili 9.5 AST 500/ALT1061
• CT large ascites, bilateral pleural effusions
• Hospitalized briefly, began to improve, labs
  essentially WNL one month later

Prob 3/Severity 3
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Ketek Pattern of toxicityAnother ascites case
2

• 37 yr old male began Ketek one wk pta
• Admitted with fever, RUQ abd pain, nausea.
• T Bili 3.9 AST 812/ALT1385 INR 1.5
• CT Prominent ascites, USG same. 800 ml clear
  fluid removed, all tests negative serologies all
  negative
• Hospitalized briefly, began to improve, labs
  essentially WNL one month later

Prob 4/Severity 3
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Charlotte casesClay et al., Ann Intern Med
20061441415

• 1) 46 yr old with dark urine on 2nd day of taking
  Ketek
• AST200/ALT948 T Bili 3.9, resolved after 8 weeks
• 2) 51 yr old physicians wife, subacute course
  beginning within a week of starting Ketek
  transplanted. Liver weighed 480 gm
• 3) 26 yr old with very acute multi-system failure
  2 wks after beginning Ketek, died 3rd hospital
  day.
• Both explant and autopsy showed massive hepatic
  necrosis

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21 hospitalized, very likely or probable
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Summary Clinical Cases

• Careful adjudication of 53 cases 5 experts
• Most cases well- or moderately well-documented
• Most confounded or insufficient data cases
  excluded
• 5 deaths/2 transplants
• 44/53 hospitalized
• 28 very likely or probable

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Conclusion Clinical Cases

• Clear-cut signal of hepatic necrosis of varying
  severity
• Certain cases have unusual signature but this
  varies
• Severity is of concern as is short latency
• Lack of confounding issues in many cases
• Adequate data in most of those reported here
• Causality assessment by a panel of experts,
  despite its shortcomings, suggests that more than
  half the cases shown here are due to Ketek

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