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Integrating functional CNS observations into toxicology studies the CONS_.ppt

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					                                  Safety Pharmacology Society Webinar Series:

                     Safety Pharmacology Endpoints: Integration into Toxicology Studies



    Integrating functional CNS observations
       into toxicology studies: the CONS!

                                   Will Redfern, PhD
                                      Safety Assessment UK
                                          Alderley Park
                                             Cheshire
                                         United Kingdom


September 20, 2012
Reasons for attrition of candidate drugs




                                                    Meanwhile, ADME failures
                                                     have been reduced by a
                                                      ‘frontloading’ approach

    Kola & Landis (2004) Nature Reviews: Drug Discovery 3: 711-715.
    Attrition due to inadequate safety – why?

Shortcoming                 Impact                              Solution?
1. Lack of early            ‘Doomed’ compounds enter in         Improve frontloaded screening: in
detection of safety         vivo tox phase                      silico and in vitro
signals
2. Lack of detection of     ‘Doomed’ compounds enter            Improve quality and increase
safety hazards              clinical development                information content of safety
preclinically                                                   pharmacology and toxicology
                                                                studies
3. Lack of                  Defective risk assessment:          Improve risk assessment and
confidence/knowledge/       ‘Doomed’ compounds may be           decision-making by better
precision in preclinical-   let through, anticipating a large   understanding of the translation of
clinical translation        safety margin; ‘safe’               the preclinical signals to humans.
                            compounds may be stopped,
                            anticipating an inadequate
                            safety margin.




                                                  3
    Attrition due to inadequate safety – why?

Shortcoming                 Impact                              Solution?
1. Lack of early            ‘Doomed’ compounds enter in         Improve frontloaded screening: in
detection of safety         vivo tox phase                      silico and in vitro
signals
2. Lack of detection of     ‘Doomed’ compounds enter            Improve quality and increase
safety hazards              clinical development                information content of safety
preclinically                                                   pharmacology and toxicology
                                                                studies
3. Lack of                  Defective risk assessment:          Improve risk assessment and
confidence/knowledge/       ‘Doomed’ compounds may be           decision-making by better
precision in preclinical-   let through, anticipating a large   understanding of the translation of
clinical translation        safety margin; ‘safe’               the preclinical signals to humans.
                            compounds may be stopped,
                            anticipating an inadequate
                            safety margin.




                                                  4
  Impact of adverse effects of drugs by organ function throughout the pharmaceutical life cycle


                                                              € €
         Phase                     ‘Nonclinical’             Phase I              Phase I-III           Phase III/                Post-                   Post-
                                                                                                        Marketing               Marketing               Marketing
                 Information:         Causes of            Serious ADRs            Causes of            ADRs on label           Serious ADRs          Withdrawal from
                                       attrition                                    attrition                                                              sale

                      Source:         Car (2006)            Sibille et al.         Olson et al.        BioPrint® (2006)          Budnitz et al.       Stevens & Baker
                                                              (1998)                 (2000)                                        (2006)                  (2008)

                 Sample size:      88 CDs stopped          1,015 subjects        82 CDs stopped          1,138 drugs           21,298 patients              47 drugs

             Cardiovascular:            27%                     9%                    21%                   36%                     15%                      45%
              Hepatotoxicity:            8%                     7%                    21%                   13%                      0%                      32%
           Haematology/BM:               7%                     2%                    4%                    16%                     10%                      9%

NERVOUS SYSTEM:                         14%                    28%                    21%                   67%                     39%                      2%
Immunotox; photosensitivity:             7%                    16%                    11%                   25%                     34%                      2%
            Gastrointestinal:            3%                    23%                    5%                    67%                     14%                      2%
                    Reprotox:           13%                     0%                    1%                    10%                      0%                      2%
                   2010 Update:
            Musculoskeletal:  4%                                0%                    1%                    28%                      3%                      2%
                 Respiratory:            2%                     0%                    0%                    32%                      8%                      2%
                       Renal:            2%                     0%                    9%                    19%                      2%                      0%
                 Genetic tox:            5%                     0%           No change in 10 years!
                                                                                     0%                      0%                      0%Increased contribution
                                                                                                                                                    0%
                                                                                                                                          from Nervous System
            Carcinogenicity:             3%                     0%                    0%                     1%                      0%        AEs in 2010
                                                                                                                                                       0%
                        Other:           0%                     0%                    4%                    16%                      2%                      2%
      The various toxicity domains have been ranked first by contribution to products withdrawn from sale, then by attrition during clinical development.

                                                      0%                       1-9%                   10-19%                       >20%
 Adapted from Redfern WS et al. SOT 2010; 2011
Impact of functional adverse effects on the nervous
    system on drug development during 2010:




                                              Source: DIA Daily
                                          January to December 2010
  Impact of functional adverse effects on the nervous
      system on drug development during 2010:




Impact of QT/TdP issues on drug development during 2010 by comparison:




                                                            Source: DIA Daily
                                                        January to December 2010
Functional measurements in repeat-dose toxicity studies

         Scientific drivers                                    Regulatory drivers
         Doing it in addition to                                   Doing it instead of
           standalone safety                                        standalone safety
         pharmacology studies                                     pharmacology studies



    Rationale:                                               Rationale:

    •To provide early warning flags well ahead               To opt for the minimum regulatory requirement
    of the regulatory GLP SP core battery                    for FTIM:
    studies (by incorporating into early tox/MTD studies).              ICHS6 (Biologics)
    •To assess whether findings in acute SP
    studies persist, intensify, or diminish after                       ICHS9 (Oncology Products)
    repeated dosing, and to demonstrate                                 FDA Guidance on Exploratory IND
    recovery after cessation of dosing.                      Studies
    •To provide functional correlates of                     by incorporating SP core battery assessments
    histopathological findings in previous tox
                                                             into the 1-month regulatory tox studies.
    studies.
    •To assess potential effects that may only
                                                             I have reservations about this. This will be
    develop after prolonged exposure.
                                                             what I’m focusing on today.


    I’m OK with this. Let’s have more of it!
                 Starting point...
• Clearly, adverse effects on the nervous system make
  a significant contribution to attrition of candidate
  drugs during clinical development.
• Therefore, the last thing we should do is reduce the
  quality of the preclinical CNS safety pharmacology
  assessment.
• So, do more ‘as well as’, and reduce the temptation
  to go for ‘instead of’*.

  *In other words, do include CNS safety pharmacology endpoints in
  repeat-dose toxicity studies as well as standalone single-dose safety
  pharmacology studies, rather than instead of.
      Why not replace standalone CNS safety
    pharmacology studies with assessments in
 repeat-dose toxicity studies – what’s the big deal?

1. The laboratory conditions in toxicology holding
   rooms/procedure rooms are not optimal for obtaining high
   quality behavioural data (due to noise; disturbance etc.).
2. The phenomenon of tolerance means that the responses
   measured on Day X may be diminished compared to Day 1 (ie,
   first administration).
3. By Day X, what you may be measuring is not the
   pharmacological response to the compound, but the effects of
   overt toxicity (inappetance; weight loss; general malaise).
4. Circumventing ‘2’ and ‘3’ above by doing the assessments on
   Day 1 of dosing causes logistical difficulties.
     Limitations of SP endpoints in tox studies


• The primary aim of a repeat-dose toxicity study is to expose
  animals to different levels of a test compound over a prolonged
  period, and to assess a standard list of in-life parameters (incl.
  clinical chemistry; body weights, food & water consumption;
  routine clinical observations; ophthalmoscopy; ECG, etc.),
  toxicokinetics, and post-mortem histological changes.
• Any additional functional measurements MUST NOT interfere
  with these aims or affect their outcome.
• The study design and laboratory conditions may be sub-optimal
  for obtaining high-quality functional data.
        Differences in in-life environments (etc.)
Safety pharmacology studies                       General toxicology studies
Dosing staggered to accommodate functional        Animals dosed all in one session (usually a.m.)
measurements
TK sample taken after key functional              TK sampling takes priority
measurements
No necropsy to consider                           Scheduled to accommodate necropsy slots

Studies powered to detect the functional effect   Studies adequate to detect histopathological
                                                  effects
Behavioural studies usually require young rats    Sexually mature animals used

Usually restricted to male animals                Equal numbers of both sexes used

May require non-standard strains (e.g.            Restricted to standard strains
pigmented rats)
Functional measurements may require pre-          Rarely required
training of animals
Functional measurements require a quiet room      Sometimes anything but!

Equipment/software may not be fully GLP-          GLP sacrosanct
compliant
Should be run by experienced safety               Toxicology facilities may be geographically
pharmacologists and technicians fully au fait     remote from available safety pharmacology
with safety pharmacology measurements and         expertise, or such expertise may not be
data interpretation                               available within the company.
Example of a custom-designed, fit-for-purpose in vivo safety pharmacology suite




         CNS
      evaluations
      done here




Features:
•Testing labs located remote from corridor noise (e.g., trundling of cage racks; loud conversations).
•Primary access to suite via single entry door, with warning to limit entry to essential visits and to minimise noise level.
•Staff requiring access to the other animals on the study can do so without disturbing the safety pharmacology
observations/measurements.
•Entry to the testing labs restricted to staff involved in the observations/measurements.
•Designed to accommodate bulky test equipment, ergonomically.
•Lighting control with local (manual) override.
               Example of toxicology study holding rooms with ante room




               CNS
            evaluations
            done here




Drawbacks (for CNS safety pharmacology observations/measurements):
•Testing area adjacent to corridor noise (e.g., trundling of cage racks; loud conversations).
•Access from corridor directly into testing area.
•Staff requiring access to the other animals on the study disturb the safety pharmacology observations/measurements.
•Entry to the testing area unrestricted.
•Bulky test equipment may be difficult to accommodate ergonomically.
•Automated lighting control with no manual override.
    Development of tolerance with repeat-dosing
    A DECREASE in response/clinical efficacy with repeat-dosing


Drug                    Therapeutic     Effects
                        target
Opiate analgesics       Pain            Rapid tolerance to most effects develops on
                                        repeat-dosing

Baclofen                Spasticity      Tolerance develops to muscle relaxant effects
                                        due to down-regulation of GABA-B receptors

Benzodiazepines         Anxiety         Tolerance develops to initial sedative effect

L-DOPA; bromocriptine   Parkinson’s     Reduced efficacy

SSRI’s                  Depression      Reduced efficacy

Haloperidol;            Schizophrenia   Reduced efficacy
chlorpromazine

Anticonvulsants         Epilepsy        Reduced efficacy




                                                                                        ‘‘Some form of adaptive
                                                                                        syndrome is the inevitable
                                                                                        consequence of the reciprocal
                                                                                        interaction between most or
                                                                                        all classes of drugs and the
                                                                                        organism’’.
                                                                                                W Haefely (1986)
Pupillary light reflex in a repeat-dose toxicology study in rats:
           tolerance developing to a mydriatic effect




                                                                                                  Drug X
                                  (slow)                                                          µmol/kg po
                                            (slow) (slow)                                         (n = 6 each)
                                                               (slow)




                                                                      (No further dosing
                                                                      at high dose level)




            Redfern WS et al. (2007) A simple method for estimating pupil diameter in conscious
            rats and dogs during repeat-dose toxicity studies. J Pharmacol Toxicol Methods 56: e50.
Saliva production in a repeat-dose toxicology study in dogs:
         tolerance developing to a salivatory effect




          Salivation quantified by placing a pre-weighed gauze swab
          inside a jowl for 20 s; removed and re-weighed.
          First measurement was on Day 3 of study. (AZ in-house data)
  Example of tolerance, increased response, and no change
   in response in the same study with the same compound!




Effects of once-daily dosing with baclofen (10 mg/kg po) in the Irwin test in rats (3M; 3F)

                               Day 1    Day 2 Day 3 Effect
              Abnormal         6/6      3/6      2/6      Diminishing
              respiration
              Decreased        6/6      6/6      6/6      Stable
              activity
              Increased        0/6      0/6      3/6      Delayed onset
              scratching

       Conclusion:
       Change in magnitude of effect over repeated dosing is both pharmacology-
       and parameter-specific – and can’t be predicted in advance.
                                                                   AZ in-house data: courtesy of Lorna Ewart
                              Logistics for rodent studies…
If you choose to go down this route (replacing the standalone safety pharmacology study), it is
preferable to conduct functional measurements on Day 1 of the repeat-dose toxicity
studies for the reasons outlined earlier (ie, you may miss an acute response that diminishes with repeat-
dosing).


But Day 1 of a tox study is usually mayhem, with timed TK bleeds etc.

So, you could do the measurements on Day 2 of the repeat-dose study.

However, you won’t get through all the Irwin tests (multiple time points) and whole-body
plethysmography (WBP) measurements (4 hours’ recordings) on the vehicle and 3 dose
levels (Irwin: 24 rats; WBP: 32 rats) in one day!

So you could do (say) the Irwin tests on Day 2 and the WBP measurements on Day 3.

Even then, you still won’t complete either of these evaluations in a single day. So you
may have to stagger the start of the rodent 1-month study, e.g.:

MON                     TUE                     WED                      THU
Day 1 Start cohort 1    Day 2 cohort 1: Irwin   Day 3 cohort 1: WBP      Day 4 cohort 1
                        Day 1 Start cohort 2    Day 2 cohort 2: Irwin    Day 3 cohort 2: WBP

And you’ll have to reduce the standard number of time points in the Irwin test.
Do you have enough quiet space to run Irwin and WBP simultaneously, close to the tox
holding room…?
                Conclusions
• Replacement of the ‘standalone’ CNS safety
  pharmacology study with ‘CNS safety pharmacology
  assessments’ in a repeat-dose tox study represents a
  dumbing-down of the preclinical CNS risk
  assessment.
• This would be like replacing the dog telemetry
  cardiovascular assessment with a ‘snapshot ECG’ in
  a tox study to assess QT risk.
• You wouldn’t do that, would you...?
                   Acknowledgements

Colleagues at AstraZeneca Alderley Park:
Sharon Storey; Helen Prior; Claire Grant; Louise Marks; Lorna
Ewart; Kat Greenwood; Claire Barnard; Dave Simpson; Sally
Robinson; Jean-Pierre Valentin.

				
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