A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions

Dopamine D3Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

“…To date, no studies on the effects of a dopamine D 3 receptor antagonist and cocaine in dogs have appeared. Dogs are a mainstay of cardiovascular safety evaluation of drugs (Pugsley et al, 2008;Ewart et al, 2013). Although it is uncertain whether the interaction between a dopamine D 3 receptor antagonist and cocaine we are reporting in dogs is predictive of a similar effect in humans, this finding would likely preclude further development of such a compound as a treatment for cocaine use disorder.…”

Incorporation of capillary microsampling into whole body plethysmography and modified Irwin safety pharmacology studies in rats

“…Dose levels were selected based on information derived from the literature (Cosmi et al, 2009) and previous studies performed in our laboratory (Ewart et al, 2013a). Four groups dosed with vehicle and clonidine were assigned to blood sampling via the standard technique and a further four groups were assigned to blood sampling via the microsampling technique.…”

“…Rats were administered the appropriate dose of vehicle or clonidine, and were then observed discretely at 0.25, 0.5, 1, 2, 4 and 24 h post-dose. Animal behavioural changes, neuromuscular, autonomic and sensorimotor signs were recorded according to a standardised observation battery (Irwin, 1968;Porsolt et al, 2007) as described in detail in a recent publication from our laboratory (Ewart et al, 2013a) and outlined in Table 1. Rectal temperature was measured at 1 h postdose, using a digital thermometer inserted 2 cm past the anal sphincter.…”

Long-term stability, reproducibility, and statistical sensitivity of a telemetry-instrumented dog model: A 27-month longitudinal assessment

“…Indeed, measurement of blood pressure in the conscious state, using radiotelemetry in freely moving animals, is considered the gold-standard technology and has been endorsed by the AHA council on high blood pressure research (Kurtz, Griffin, Bidani, Davisson, & Hall, 2005) and international regulatory agencies (ICH S7A) prior to FIH testing of novel therapeutics. While multi-site comparisons of in vivo safety pharmacology studies conducted in telemetry dog to support ICH S7A and S7B regulatory submissions have yielded similar results (Ewart et al, 2013;Sasaki, Shimizu, Suganami, & Yamamoto, 2005), few have investigated the long-term stability of hemodynamic and ECG endpoints at baseline, reproducibility in response to pharmacologic challenge, and maintenance of statistical sensitivity, over the usable-life of the colony. These questions were addressed in 3 identical studies spanning 27 months that were performed in the same colony of instrumented dogs.…”