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2008-4369s1-03-Guest- Hamlin by yaofenji

VIEWS: 3 PAGES: 19

									The inability to predict
toxicity with 100 percent
sensitivity and specificity
may be tragic, expensive
and embarrassing….a
discussion in the context
of animal models.
Serious cardiopulmonary reactions, including
fatalities, have occurred during or following
perflutren-containing microsphere
administration. The risk for these reactions
may be increased among patients with
pulmonary hypertension or unstable
cardiopulmonary conditions (acute myocardial
infarction, acute coronary artery syndromes,
worsening or unstable congestive heart failure,
serious ventricular arrhythmias or respiratory
failure,
   Identifying a toxic potential is a
            daunting task.
You don’t give drugs to normal people!
  Robert L. Hamlin, DVM, PhD, DACVIM (Cardiology/Internal Medicine)
  Stanton Youngberg Professor of Physiology/Pharmacology, Professor
  Biomedical Engineering, Professor Davis Heart and Lung Research
  Institute, Ohio State University, Scientific Director, QTest Labs, LLC.




                            In a life time, heart beats 2.4 billion times
                            for man, 1.2 billion times for cat, and only,
                            600 million times for all other species.
Daunting because of:
• rare occurrence (e.g., 1:100,000 for terfenadine),
• insidious onset (e.g., years for fen-phen or
  doxorubicin)
• many potential targets and variations
  (polymorphisms) in the targets (e.g., long QT,
  Brugada syndrome)
• hysteresis (e.g., different “on” from “off”!),
• differing responses dependent upon state of
  health or specific diseases (e.g., diabetics,
  patients with heart failure or diabetes, obese)
• logistics (e.g., costs, regulations, animal rights
  activists, cleverness, communication)
• using inappropriate surrogates (e.g., rat for
  terfenadine, dog for procainamide, rabbit
  for atropine, pig for exercise)
• using inappropriate preparations (e.g.,
  restraint, temperature, instrumentation,
  husbandry, excipients)
      What constitutes toxicity….
        different from health?
• Health—feel good and live long (120 years)
• Disease—feel bad and/or do not live long (e.g.,
  coronary artery disease, cancer, diabetes)
• Absence of health—do not necessarily feel bad
  but don’t live to full longevity or a life of good
  quality (e.g., 110<SAP<140 mmHg; 60-
  101<glucose<102<140 mg%;
  130<cholesterol<200 mg%); ?premature
  depolarizations)
The “best” surrogate can be identified best by regulatory
agencies who by experience have identified it as predicting,
with highest sensitivity and specificity, the likelihood of a
toxic reaction in man.

You can know all there is to know about mechanisms of disease,
and all there is to know about mechanisms by which a
therapeutic agent works, but the only way to know if it does
work is to give it in a clinically relevant manner to a target
species with the specific disease for which it is indicated.
modified from Bernard Lown

The “best” surrogate may be “best’ only for a specific
test article, for a specific disease, and in a specific patient.

Therefore this presentation is doomed from the outset!
       How drugs/diseases affect all properties.


          *                                   **   hindrance




                * rate, force



   *                                           *       H2O     *
                                              UV
                                                     *
TV
f
dif.   *   hindrance
                                                   **
                                                    capacity
                                rate, force
Do these individuals look alike? Is there any reason to believe that
they act alike, or that their physiological or pathophysiological
processes are alike? Clearly, no!
If you are lucky, you study a
human population
heterogeneous enough to
extrapolate results to the
general population.
Do these individuals look alike? Is there any reason to believe that
they act alike, or that their physiological or pathophysiological
processes are alike….or that findings on one may be extrapolated
to another?
If you are lucky enough, you pick
animal surrogates that possess
physiology close enough to human
that the results matter.
Is it reasonable to believe that information
gleaned from a healthy mouse raised in
a foreign environment is extrapolatable to
a sick person?

Corollary question: How many of you would
conduct clinical trials on persons all at
20 degrees Fahrenheit?
                                                                                                                                                                 rabbit?




                                                  Steve Swoap
                                                  Williams College
                                                                                                                                                                                                                                                                             taken at 10 PM?
                                                                                                                                                                                                                                                                             Why do you dose




                                                                             “freezing” mouse?
                                                                                                                                                                                                                                                                             between 8 AM and



                                                                                                                                                                 Why would you study

                                                                                                                                                                 or an IKS blocker in a




                         RL Hamlin, 2008
                                                                                                                                                                 an IKR blocker in a rat
                                                                                                                                                                                                                                                                             10 AM for a drug to be




                                                                             a study conducted on a
                                                                             What can you trust from
                                                                                                                                              MAP (mmHg)                                                                          VO2 (ml/min)
                                                                                                                                                                                                                                                                     C




                                                             Activity (m)                                                                                                                                                                                                                                          Heart Rate (bpm)




                                                                                           G
                                                                                                                               50
                                                                                                                                    60
                                                                                                                                         70
                                                                                                                                                80
                                                                                                                                                     90
                                                                                                                                                          100
                                                                                                                                                                 110
                                                                                                                                                                       E 120
                                                                                                                                                                                                            0.25
                                                                                                                                                                                                                    0.50
                                                                                                                                                                                                                            0.75
                                                                                                                                                                                                                                      1.00
                                                                                                                                                                                                                                              1.25
                                                                                                                                                                                                                                                      1.50
                                                                                                                                                                                                                                                              1.75
                                                                                                                                                                                                                                                                      2.00
                                                                                                                                                                                                                                                                                                       100
                                                                                                                                                                                                                                                                                                             200
                                                                                                                                                                                                                                                                                                                   300
                                                                                                                                                                                                                                                                                                                         400
                                                                                                                                                                                                                                                                                                                               500
                                                                                                                                                                                                                                                                                                                                     600
                                                                                                                                                                                                                                                                                                                                           700
                                                                                                                                                                                                                                                                                                                                                 A 800




                               0.00
                                           0.25
                                                      0.50
                                                               0.75
                                                                      1.00
                                                                             1.25
                                                                                    1.50
                                                                                              1.75
                                                                                                                      -1                                                                          -1                                                                                          -1
                     -1                                                                                                  .0                                                                          .0                                                                                          .0
                        .0                                                                                            -0 0                                                                        -0 0                                                                                        -0 0
                     -0 0                                                                                                .7                                                                          .7                                                                                          .7
                        .7                                                                                            -0 5                                                                        -0 5                                                                                        -0 5
                     -0 5                                                                                                .5                                                                          .5                                                                                          .5
                        .5                                                                                            -0 0                                                                        -0 0                                                                                        -0 0
                     -0 0                                                                                                .2                                                                          .2                                                                                          .2
                        .2                                                                                             0. 5
                      0. 5                                                                                                0                                                                        0. 5
                                                                                                                                                                                                      0                                                                                        0. 5
                                                                                                                                                                                                                                                                                                  0
                         0                                                                                             0. 0
                      0. 0                                                                                                2                                                                        0. 0
                                                                                                                                                                                                      2                                                                                        0. 0
                                                                                                                                                                                                                                                                                                  2
                         2                                                                                             0. 5
                      0. 5                                                                                                5                                                                        0. 5
                                                                                                                                                                                                      5                                                                                        0. 5
                                                                                                                                                                                                                                                                                                  5
                         5                                                                                             0. 0
                      0. 0                                                                                                7                                                                        0. 0
                                                                                                                                                                                                      7                                                                                        0. 0
                                                                                                                                                                                                                                                                                                  7
                         7                                                                                             1. 5
                      1. 5                                                                                                0                                                                        1. 5
                                                                                                                                                                                                      0                                                                                        1. 5
                                                                                                                                                                                                                                                                                                  0
                         0                                                                                             1. 0
                      1. 0                                                                                                2                                                                        1. 0
                                                                                                                                                                                                      2                                                                                        1. 0
                                                                                                                                                                                                                                                                                                  2
                         2                                                                                             1. 5
                      1. 5                                                                                                5                                                                        1. 5
                                                                                                                                                                                                      5                                                                                        1. 5
                                                                                                                                                                                                                                                                                                  5
                         5                                                                                             1. 0
                      1. 0                                                                                                7                                                                        1. 0
                                                                                                                                                                                                      7                                                                                        1. 0
                                                                                                                                                                                                                                                                                                  7
                         7                                                                                             2. 5
                      2. 5                                                                                                0                                                                        2. 5
                                                                                                                                                                                                      0                                                                                        2. 5
                                                                                                                                                                                                                                                                                                  0
                         0                                                                                             2. 0
                      2. 0                                                                                                2                                                                        2. 0
                                                                                                                                                                                                      2                                                                                        2. 0
                                                                                                                                                                                                                                                                                                  2
                         2                                                                                             2. 5
                                                                                                                          5                                                                        2. 5                                                                                        2. 5
                                                                                                     Time (hours)

                                                                                                                                                                                                      5
                                                                                                                                                                               Time (hours)




                                                                                                                                                                                                                                                                                                  5
                                                                                                                                                                                                                                                                               Time (hours)




                      2. 5
                         5




Time (hours)
                                                                                                                       2. 0
                      2. 0                                                                                                7                                                                        2. 0
                                                                                                                                                                                                      7                                                                                        2. 0
                                                                                                                                                                                                                                                                                                  7
                         7                                                                                             3. 5
                      3. 5                                                                                                0                                                                        3. 5
                                                                                                                                                                                                      0                                                                                        3. 5
                                                                                                                                                                                                                                                                                                  0
                         0                                                                                             3. 0
                      3. 0                                                                                                2                                                                        3. 0
                                                                                                                                                                                                      2                                                                                        3. 0
                                                                                                                                                                                                                                                                                                  2
                         2                                                                                             3. 5
                      3. 5                                                                                                5                                                                        3. 5
                                                                                                                                                                                                      5                                                                                        3. 5
                                                                                                                                                                                                                                                                                                  5
                         5                                                                                             3. 0
                      3. 0                                                                                                7                                                                        3. 0
                                                                                                                                                                                                      7                                                                                        3. 0
                                                                                                                                                                                                                                                                                                  7
                         7                                                                                             4. 5
                      4. 5                                                                                                0                                                                        4. 5
                                                                                                                                                                                                      0                                                                                        4. 5
                                                                                                                                                                                                                                                                                                  0
                         0                                                                                             4. 0
                      4. 0                                                                                                2                                                                        4. 0
                                                                                                                                                                                                      2                                                                                        4. 0
                                                                                                                                                                                                                                                                                                  2
                         2                                                                                             4. 5
                      4. 5                                                                                                5                                                                        4. 5
                                                                                                                                                                                                      5                                                                                        4. 5
                                                                                                                                                                                                                                                                                                  5
                         5                                                                                             4. 0                                                                        4. 0                                                                                        4. 0
                      4. 0                                                                                                75                                                                          75                                                                                          75
                         75
                                                                                                                               18
                                                                                                                                    20
                                                                                                                                         22
                                                                                                                                                24
                                                                                                                                                     26
                                                                                                                                                          28
                                                                                                                                                                 30
                                                                                                                                                                         32
                                                                                                                                                                                                           18
                                                                                                                                                                                                                   20
                                                                                                                                                                                                                           22
                                                                                                                                                                                                                                     24
                                                                                                                                                                                                                                             26
                                                                                                                                                                                                                                                     28
                                                                                                                                                                                                                                                             30
                                                                                                                                                                                                                                                                     32
                                                                                                                                                                                                                                                                                                       18
                                                                                                                                                                                                                                                                                                             20
                                                                                                                                                                                                                                                                                                                   22
                                                                                                                                                                                                                                                                                                                         24
                                                                                                                                                                                                                                                                                                                               26
                                                                                                                                                                                                                                                                                                                                     28
                                                                                                                                                                                                                                                                                                                                           30
                                                                                                                                                                                                                                                                                                                                                   32




                              18
                                           20
                                                     22
                                                               24
                                                                      26
                                                                             28
                                                                                    30
                                                                                              32




                                                     Temperature (C)                                                                     Temperature (C)                                                                    Temperature (C)                                                                        Temperature (C)

                                                                                                                                                                                                                                  VO2 (ml/min)                                                                     Heart Rate (bpm)
                                                                                                                                                                                                                                                                     D




                                                             Activity (m)                                                                     MAP (mmHg)
                                                                                                                                                                                                                                                                                                       100
                                                                                                                                                                                                                                                                                                             200
                                                                                                                                                                                                                                                                                                                   300
                                                                                                                                                                                                                                                                                                                         400
                                                                                                                                                                                                                                                                                                                               500
                                                                                                                                                                                                                                                                                                                                     600
                                                                                                                                                                                                                                                                                                                                           700
                                                                                                                                                                                                                                                                                                                                                 B 800




                                                                                                                                                                                                           0.25
                                                                                                                                                                                                                   0.50
                                                                                                                                                                                                                           0.75
                                                                                                                                                                                                                                     1.00
                                                                                                                                                                                                                                             1.25
                                                                                                                                                                                                                                                     1.50
                                                                                                                                                                                                                                                             1.75
                                                                                                                                                                                                                                                                     2.00




                                                                                                                               50
                                                                                                                                    60
                                                                                                                                         70
                                                                                                                                                80
                                                                                                                                                     90
                                                                                                                                                           100
                                                                                                                                                                 110
                                                                                                                                                                       F 120




                                                                                                                                                                                                                                                                                              -1
                              0.00
                                           0.25
                                                     0.50
                                                               0.75
                                                                      1.00
                                                                             1.25
                                                                                    1.50
                                                                                           H 1.75




                                                                                                                                                                                                 -1                                                                                              .0
                                                                                                                      -1                                                                                                                                                                      -0 0
                     -1                                                                                                  .0                                                                         .0                                                                                           .7
                        .0                                                                                            -0 0                                                                       -0 0                                                                                         -0 5
                     -0 0                                                                                                .7                                                                         .7                                                                                           .5
                        .7                                                                                            -0 5                                                                       -0 5                                                                                         -0 0
                     -0 5                                                                                                .5                                                                         .5                                                                                           .2
                        .5                                                                                            -0 0                                                                       -0 0
                     -0 0                                                                                                .2                                                                         .2                                                                                         0. 5
                                                                                                                                                                                                                                                                                                  0
                        .2                                                                                             0. 5                                                                       0. 5
                      0. 5                                                                                                0                                                                          0                                                                                         0. 0
                                                                                                                                                                                                                                                                                                  2
                         0                                                                                             0. 0                                                                       0. 0
                      0. 0                                                                                                2                                                                          2                                                                                         0. 5
                                                                                                                                                                                                                                                                                                  5
                         2                                                                                             0. 5                                                                       0. 5
                      0. 5                                                                                                5                                                                          5                                                                                         0. 0
                                                                                                                                                                                                                                                                                                  7
                         5                                                                                             0. 0                                                                       0. 0
                      0. 0                                                                                                7                                                                          7                                                                                         1. 5
                                                                                                                                                                                                                                                                                                  0
                         7                                                                                             1. 5                                                                       1. 5
                      1. 5                                                                                                0                                                                          0                                                                                         1. 0
                                                                                                                                                                                                                                                                                                  2
                         0                                                                                             1. 0                                                                       1. 0
                      1. 0                                                                                                2                                                                          2                                                                                         1. 5
                                                                                                                                                                                                                                                                                                  5
                         2                                                                                             1. 5                                                                       1. 5
                      1. 5                                                                                                5                                                                          5                                                                                         1. 0
                                                                                                                                                                                                                                                                                                  7
                         5                                                                                             1. 0                                                                       1. 0
                      1. 0                                                                                                7                                                                          7                                                                                         2. 5
                                                                                                                                                                                                                                                                                                  0
                         7                                                                                             2. 5                                                                       2. 5
                      2. 5                                                                                                0                                                                          0                                                                                         2. 0
                                                                                                                                                                                                                                                                                                  2
                         0                                                                                             2. 0                                                                       2. 0
                                                                                                                          2                                                                          2                                                                                         2. 5
                                                                                                                                                                                                                                                                                                  5
                                                                                                                                                                                                                                                                             Time (hours)




                      2. 0
                         2                                                                                                                                                                        2. 5
                                                                                                                                                                                   Tim (hours)




                                                                                                                       2. 5                                                                          5                                                                                         2. 0
                                                                                                                          5                                                                                                                                                                       7
                                                                                                       Time (hours)




                      2. 5
                         5
      Time (hours)




                                                                                                                       2. 0                                                                       2. 0
                      2. 0                                                                                                7                                                                          7                                                                                         3. 5
                                                                                                                                                                                                                                                                                                  0
                         7                                                                                             3. 5                                                                       3. 5
                      3. 5                                                                                                0                                                                          0                                                                                         3. 0
                                                                                                                                                                                                                                                                                                  2
                         0                                                                                             3. 0                                                                       3. 0
                      3. 0                                                                                                2                                                                          2                                                                                         3. 5
                                                                                                                                                                                                                                                                                                  5
                         2                                                                                             3. 5                                                                       3. 5
                      3. 5                                                                                                5                                                                          5                                                                                         3. 0
                                                                                                                                                                                                                                                                                                  7
                         5                                                                                             3. 0                                                                       3. 0
                      3. 0                                                                                                7                                                                          7                                                                                         4. 5
                                                                                                                                                                                                                                                                                                  0
                         7                                                                                             4. 5                                                                       4. 5
                      4. 5                                                                                                0                                                                          0                                                                                         4. 0
                                                                                                                                                                                                                                                                                                  2
                         0                                                                                             4. 0                                                                       4. 0
                      4. 0                                                                                                2                                                                          2                                                                                         4. 5
                                                                                                                                                                                                                                                                                                  5
                         2                                                                                             4. 5                                                                       4. 5
                      4. 5                                                                                                5                                                                          5                                                                                         4. 0
                         5                                                                                             4. 0                                                                       4. 0
                                                                                                                                                                                                                                                                                                  75
                      4. 0                                                                                                75                                                                         75
                         75
                                                                                                                                                                                                                                                                                                       18
                                                                                                                                                                                                                                                                                                             20
                                                                                                                                                                                                                                                                                                                   22
                                                                                                                                                                                                                                                                                                                         24
                                                                                                                                                                                                                                                                                                                               26
                                                                                                                                                                                                                                                                                                                                     28
                                                                                                                                                                                                                                                                                                                                           30
                                                                                                                                                                                                                                                                                                                                                   32




                                                                                                                                                                                                           18
                                                                                                                                                                                                                   20
                                                                                                                                                                                                                           22
                                                                                                                                                                                                                                    24
                                                                                                                                                                                                                                             26
                                                                                                                                                                                                                                                     28
                                                                                                                                                                                                                                                             30
                                                                                                                                                                                                                                                                     32




                                                                                                                               18
                                                                                                                                    20
                                                                                                                                         22
                                                                                                                                                24
                                                                                                                                                     26
                                                                                                                                                           28
                                                                                                                                                                 30
                                                                                                                                                                         32




                              18
                                           20
                                                     22
                                                               24
                                                                      26
                                                                             28
                                                                                    30
                                                                                             32




                                                                                                                                                                                                                                                                                                                   Temperature (C)
                                                                                                                                         Temperature (C)                                                                   Temperature (C)
                                                     Temperature (C)
                     Clotting Profile
              man    chimp   monk       pig        dog        cat        rat
I       mg%   100                       300                   500        400
II      U     1
V       U     1                         5          6          12         2
VII     U     1                         2          5          6
X       U     1                         2          2          3
VIII    U     1                                    4          19
IX      U     1                         0.6
XI      U     1                         0.3        3          3
XII     U     1      3                  5                     2
Flet    U     1      ?                             0.3        0.1
Fitz    U     1      ?                  3          0.3        ?          0.3
ATIII   U     1
XIII    R     10     ?       34         21                    ?

              man    chimp    monkey     pig        dog        cat        rat
 BT     m     3.75            3.75       2          3.5        2          3
 CT     m     9      6        5          7          4          6          3.5
 PTs    m     12     11.5     11.5       12.5       11         12         11


                             J H Lewis, Comparative Hemostasis in Vertebrates
                             Plenum Press, New York, 1996
The “best” surrogate can be identified best by regulatory
agencies who by experience have identified it as predicting,
with highest sensitivity and specificity, the likelihood of a
toxic reaction in man.

You can know all there is to know about toxicity, and all there
is to know about the pharmacology of a drug, but the only
way to know if it is toxic is to give it in a clinically relevant
manner to a target species with the specific disease for
which it is indicated. modified from Bernard Lown

The “best” surrogate may be “best’ only for a specific
test article, for a specific disease, and in a specific patient.

Therefore this presentation is doomed from the outset!
         The final question!
What is the best model to predict the toxic
potential for a test article? To answer you
must know: (1) What the potential target(s)
of toxicity is(are)? (2) How do those
targets vary among recipients/surrogates?
(3) The precise conditions of use of the
test article.
One thing is true….for certain! Preclinical trials
are important to protect subjects of clinical
trials, because: higher exposures can be used,
they provide clinical investigators with hints as
to what targets should be explored, they
frequently do expose toxicities.

Our job, however, is to identify the appropriate
surrogates for man.

A daunting task, indeed!

								
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