Hepatic Effects of Ketek Telithromycin by mikeholy

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

                           1
    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
                                    2
                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




                                                   3
                  Phase I
 Ketek        Single-Dose     Multiple-Dose
 Dose           Studies           Studies
  (mg)        Hepatic AEs      Hepatic AEs
            n/N       (%)    n/N         (%)
 50-200     0/19       0     0/16          0
400-600     0/64       0     0/53          0
    800    5/401       1    1/170         <1
    900       -         -     0/8          0
   1200     0/8        0     0/10          0
   1600     0/74       0     0/24          0
   2000     3/16       19      -           -
   2400     0/47       0       -           -
   3200     1/24       4       -           -
   Total   9/653       1    1/281         <1
Placebo    1/98       1     0/42         0
                                               4
                    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


                                                    5
                   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

                                                     6
   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




                                                     7
   AST Changes at On-Therapy (Day 2 to 5) in
   Patients Normal at Baseline – CAP Studies


                                 Ketek      Comparators*
Changes in AST                   N=320          N=314
     (ULN)                     n      %       n       %
<1x                           284     89     293     93
>1x & < 2x                     33      10    18      6
>2x & < 3x                      1      <1    1      <1
>3x & < 5x                      2      <1    2      <1
>5x                             0      0     0      0
* Clarithromycin 500 mg po bid x 10d
  Amoxicillin 1000 mg po tid x 10d,
  Trovafloxacin 200 mg po qd x 7-10d                       8
AST Changes at Post-Therapy (Day 17 to 21) in
 Patients Normal at Baseline – CAP Studies


                                    Ketek     Comparators*
   Changes in AST                   N=296         N=293
        (ULN)                     n      %      n       %
   <1x                           275    93     287      98
   >1x & < 2x                     18     6     6      2
   >2x & < 3x                      2     <1    0       0
   >3x & < 5x                      1     <1    0       0
   >5x                             0      0    0       0
  * Clarithromycin 500 mg po bid x 10d
    Amoxicillin 1000 mg po tid x 10d,
                                                       9
    Trovafloxacin 200 mg po qd x 7-10d
ALT Changes at On-Therapy (Day 2 to 5) in
Patients Normal at Baseline – CAP Studies



                                  Ketek     Comparators*
Changes in ALT                   N=320          N=314
     (ULN)                      n      %      n       %
< 1x                           279     87    283      90
>1x & < 2x                     35      11    28      9
>2x & < 3x                      5       2    2      <1
>3x & < 5x                      1      <1    0      0
>5x                             0       0    1      <1
* Clarithromycin 500 mg po bid x 10d
  Amoxicillin 1000 mg po tid x 10d,                  10
  Trovafloxacin 200 mg po qd x 7-10d
ALT Changes at Post-Therapy (Day 17 to 21) in
 Patients Normal at Baseline – CAP Studies


                                 Ketek       Comparators*
  Changes in ALT                 N=296           N=293
       (ULN)                   n     %         n       %
  < 1x                        256    86       265      90
  >1x & < 2x                   36       12    27      9
  >2x & < 3x                    4       1      0     0
  >3x & < 5x                    0       0      1     <1
  >5x                           0       0      0     0
 * Clarithromycin 500 mg po bid x 10d
   Amoxicillin 1000 mg po tid x 10d,
                                                      11
   Trovafloxacin 200 mg po qd x 7-10d
Combined ALT/AST & T. Bili. Abnormalities
          > ULN & < 2xULN


    Lab Analytes
                       Ketek    Comparators

 AST & ALT & T.Bili.   5/2358     0/1224
    ALT & T. Bili.     5/2358     0/1224
    AST & T. Bili.     1/2358     0/1224



                                           12
    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)
                                                       13
Serious Adverse Events
   Phase III Studies




                         14
     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



                                                15
     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
                                        
Analyte      Normal Range Day 1 Day 5       Day 7 Day 12
AST          (9-34 U/L)    37    295          66    24
ALT          (6-32 U/L)    24    418         200    64
T. Bili.     (3-21 umol/L) 17     22          10     -
Alk. Phos.   (35-115 U/L)  79    146         131     -


                                                       16
     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
                                      
                             Day   Day    Day   Day   Day
Analyte      Normal Range
                              1     4      13   21    31
AST          (11-36 U/L)     23    ND     273   29    19
ALT          (6-43 U/L)      27    ND     124   44    28
T. Bili.     (3-21 umol/L)   21    ND      14   22    15
Alk. Phos.   (<250 U/L)      93    ND      79   79    79
GGT          (10-61 U/L)     31    ND      37   39    35
                                                      17
     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
                                
Analyte     Normal Range Day 1 Day 21 Day 24 Day 35
AST         (<49 U/L)       38     -     -      -
ALT         (<49 U/L)       81    354  1529   518
T. Bili.    (2-20 umol/L)    9     nl   29     15
Alk. Phos. (60-275 U/L)      nl    nl  169    261
Eosinophils (<500 cells/uL) 774   960  1062   2856

                                                  18
     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
                                                    19
Review of the Pathology

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

                                       20
  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


                                                     21
 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


                                                      22

								
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