Advantages of Conducting a Stand-Alone Respiratory Safety Pharmacology Study Dennis J. Murphy, PhD, DABT Director - Safety Pharmacology US GlaxoSmithKline Pharmaceuticals

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

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 n=3/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