1 / 22

Hepatic Effects of Ketek (Telithromycin)

Hepatic Effects of Ketek (Telithromycin). Edward Cox, MD, MPH Medical Officer FDA. Ketek - Hepatic Effects. Overview Pre-Clinical Studies Phase I Studies in Humans Phase III Data Adverse Events (AEs) Analysis of Laboratory Data Serious Adverse Events (SAEs) Summary of the Findings.

vesna
Download Presentation

Hepatic Effects of Ketek (Telithromycin)

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Hepatic Effects of Ketek (Telithromycin) Edward Cox, MD, MPH Medical Officer FDA

  2. Ketek - Hepatic Effects Overview • Pre-Clinical Studies • Phase I Studies in Humans • Phase III Data • Adverse Events (AEs) • Analysis of Laboratory Data • Serious Adverse Events (SAEs) • Summary of the Findings

  3. Pre-Clinical • Hepatotoxicity in Rats, Dogs, and Monkeys • Increased AST & ALT • Hepatic necrosis in 4-week rat study • Hepatocellular hypertrophy & multinucleated hepatocytes • Hepatic Effects of Ketek more than clarithromycin

  4. Phase I

  5. Phase I Study 1030 • 8 Elderly Subjects • Single doses 1200, 1600, 2000 mg Ketek and placebo • 3 with ALT/AST 100-300 U/L (ALT>AST) • 72yo F 7-days post 2000 mg • 69yo M 17-days post 2000 mg • 62yo M 7-days post placebo (14-days post 2000 mg) • Possible Drug-Effect w/ 7-17 day latency period

  6. Phase III • Hepatic Adverse Events (AEs) Rates • Similar for Ketek and Comparators • Treatment Discontinuation Rates for Hepatic AEs • Similar for Ketek and Comparators • Serious Hepatic AEs • Comp Studies - Ketek 2 vs. Comparators 1 • Non-Comp Studies - 1 Ketek serious AE • Hepatic Deaths • No Deaths Attributed to Drug-Induced Hepatic Injury

  7. Laboratory Abnormalities • Comparative Studies in Patients Normal at Baseline • AST and ALT changes • CAP Studies - more AST & ALT elevations at On-Therapy and Post-Therapy in Ketek Arm • Non-CAP Studies - Ketek & comparator similar

  8. AST Changes at On-Therapy (Day 2 to 5) in Patients Normal at Baseline – CAP Studies

  9. AST Changes at Post-Therapy (Day 17 to 21) in Patients Normal at Baseline – CAP Studies

  10. ALT Changes at On-Therapy (Day 2 to 5) in Patients Normal at Baseline – CAP Studies

  11. ALT Changes at Post-Therapy (Day 17 to 21) in Patients Normal at Baseline – CAP Studies

  12. Combined ALT/AST & T. Bili. Abnormalities > ULN & < 2xULN

  13. Combined ALT/AST & T. Bili. Abnormalities • Drug-induced hepatocellular injury w/ overt jaundice - mortality of at least 10% - “Hy’s Law” • AST or ALT > 3xULN & T. Bili >1.5xULN Ketek • ALT 19x ULN & T. Bili. 1.55x ULN* • AST 3.1x ULN & T. Bili. 1.48x ULN • AST 2.8x ULN & T. Bili. 1.48x ULN Comparator • None * Local Lab Data, ALT 81 at baseline (NR<49 U/L)

  14. Serious Adverse EventsPhase III Studies

  15. Serious Adverse Events Comparator SAE #1 • 61 yo male w/ CAP & h/o CHF & EtOHism on Digoxin • Treated w/Clarithromycin 500mg po BID Day 1-10 • Jaundiced on Day 17 - CT Scan and U/S exams disseminated neoplasm - hepatic vs. renal origin • T.Bili. 103 umol/L (NR 3-21) • Alk. Phos. 658 U/L (NR <121) • AST & ALT normal

  16. Serious Adverse Events Ketek #1 76 yo Female w/ CAP & h/o hyperchol. & hyperuricemia on pravastatin 20 mg po QD and allopurinol 20 mg po QD chronically. Treated w/ Ketek 800 mg po QD on Day 1 thru 6

  17. Serious Adverse Events • Ketek #2 • 19 yo male w/TonsPhar +GABHS & no Sig. PMHx • Treated w/ Ketek 800 mg po QD Day 1 - 5 • Evening of Day 12 - EtOH

  18. Serious Adverse Events Ketek # 3 53 yo male w/ CAP & h/o Asthma & DM on inhaled salbutamol, fluticasone, Atrovent,Nasonex, and po Ca++. Acetaminophen Day 13 - ? Treated w/ Ketek 800 mg po QD on Day 1 thru 10. Day 14 fever/vomiting/diarrhea - fever persists

  19. Serious Adverse Events Ketek # 3 (cont’d) • Serologies for Hepatitis A, B, and C - negative • Liver Biopsy on Day 29 • ALT nearly normalized by 3 months • 2nd Event - 8 months after the 1st - ALT 1331 • Anti-smooth muscle antibodies + at 1:1000 • Elevated IgG and IgA • No Eosinophilia • 2nd Liver Biopsy at 9 months

  20. Review of the Pathology Zachary D. Goodman, MD, PhD Chief, Division of Hepatic Pathology Armed Forces Institute of Pathology Department of Defense

  21. Summary of Ketek - Hepatic Effects • Pre-Clinical • Hepatotoxicity in Dogs, Rats, Monkeys • Phase I • Clustering of hepatic AEs in elderly at 2000 mg x1 • No clear dose-response for hepatic AEs • Phase III • Similar AE rates Ketek and Comparators • No apparent drug-induced hepatic deaths

  22. Summary of Ketek - Hepatic Effects • Phase III (cont’d) • 2 Hepatic SAEs plausibly assoc. with Ketek • 1 of these events w/centrilobular necrosis and eosinophilic infiltration (ALT & Eos  Day 1) • More AST and ALT elevations in Ketek-treated CAP patients with normal baseline values • Not seen in Non-CAP patients • Concomitant Low-Level AST / ALT & T.Bili. elevations only in Ketek treated patients

More Related