Advantages of Conducting a Stand-Alone Respiratory Safety Pharmacology Study

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Advantages of Conducting a Stand-Alone
Respiratory Safety Pharmacology Study

• Dennis J. Murphy, PhD, DABT
• Director - Safety Pharmacology US
• GlaxoSmithKline Pharmaceuticals

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Advantages

• Ventilatory measurements in animal models can be
  highly variable due primarily to a sensitivity to
  environmental changes (stimuli)
• Stimuli include noise, odor, movement, handling,
  light, temperature
• As such, measurements require a highly controlled
  environment for accurate and repeatable
  measurements
• This can be achieved in a stand-alone study
• Very difficult to achieve in a typical toxicology
  study where many activities are constantly
  ongoing and high number of animals are involved
• Stand-alone studies allow the use of animals with
  a telemetry implant for measuring body
  temperature and pleural pressure (required to
  obtain a direct measure of airway resistance)
• Generally not acceptable in a toxicology study
  due to pathology complications and resource
  limitations

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Advantages (continued)

• Stand-alone studies have greater flexibility in
  study design
• Can use either crossover designs (animals serve
  as their own control) or parallel design with n
  6-8 of single sex per dose group
• Can include recovery time for assessing
  reversibility or delayed effects (beyond 24 hrs
  post dose)
• A typical 2/4 week toxicology study can be
  limited to a parallel design with n3/sex per
  dose group (non-rodent) (sufficient for
  statistical analysis?) and may not include a
  recovery period (rodent or non-rodent)
• Acute (day 1) measurements can be obtained with
  stand-alone studies
• Day 1 measurements are critical because of
  tachyphylaxis or tolerance/compensation that can
  develop on repeat dosing
• This can be difficult in toxicology studies
  because of TK analysis and enhanced clinical
  observations that need to be conducted on day1