Effects of group housing on ECG assessment in conscious cynomolgus monkeys.

INTRODUCTION: Assessing the cardiovascular safety of new chemical or biological entities is important during pre-clinical development. Electrocardiogram (ECG) assessments in non-human primate (NHP) toxicology studies are often made using non-invasive telemetry systems. We investigated whether ECG recording was feasible during group housing of NHPs, rather than the usual single housed arrangement, and whether it would impact the data collected or affect the ability to detect drug-induced changes in QTc interval. METHODS: Following a period of acclimatisation to jackets, cynomolgus monkeys (3 males and 3 females) were housed in same sex groups of 3. Female monkeys were administered 4 doses of vehicle while male monkeys were administered vehicle, 15, 45, and 135mg/kg moxifloxacin. Each dose was administered on a separate dosing day. The same dosing protocol was repeated with the animals singly housed and the results from the two phases were compared including assessment of statistical power. RESULTS: Heart rate (HR) was significantly lower, and PR and QT intervals were significantly higher, at multiple time points when the animals were group housed compared with the singly housed phase. QRS duration and QTc interval were less affected. Moxifloxacin increased QT and QTc intervals but had no consistent effect on HR, QRS duration or PR interval under group housed or singly housed conditions. Power analysis suggested that group housing did not adversely affect the magnitude of detectable changes of ECG parameters. In general, detection of slightly smaller changes was achieved under conditions of group housing. DISCUSSION: The current study shows group housing to be technically possible during non-invasive ECG recording, resulting in lower resting heart rates and small improvements in sensitivity of detection of drug-induced effects. Given the psychological benefits of group housing for NHPs, it is a refinement that should be considered when conducting ECG assessments in NHP toxicology studies.

Effects of group housing on ECG assessment in conscious cynomolgus monkeys.

INTRODUCTION: Assessing the cardiovascular safety of new chemical or biological entities is important during pre-clinical development. Electrocardiogram (ECG) assessments in non-human primate (NHP) toxicology studies are often made using non-invasive telemetry systems. We investigated whether ECG recording was feasible during group housing of NHPs, rather than the usual single housed arrangement, and whether it would impact the data collected or affect the ability to detect drug-induced changes in QTc interval. METHODS: Following a period of acclimatisation to jackets, cynomolgus monkeys (3 males and 3 females) were housed in same sex groups of 3. Female monkeys were administered 4 doses of vehicle whilst male monkeys were administered vehicle, 15, 45 and 135mg/kg moxifloxacin. Each dose was administered on a separate dosing day. The same dosing protocol was repeated with the animals singly housed and the results from the two phases were compared including assessment of statistical power. RESULTS: Heart rate (HR) was significantly lower, and PR and QT interval significantly higher, at multiple time points when the animals were group housed compared with the singly housed phase. QRS duration and QTc interval were less affected. Moxifloxacin increased QT and QTc intervals but had no consistent effect on HR, QRS duration or PR interval under group housed or singly housed conditions. Power analysis suggested that group housing did not adversely affect the magnitude of detectable changes of ECG parameters. In general, detection of slightly smaller changes was achieved under conditions of group housing. DISCUSSION: The current study shows group housing to be technically possible during non-invasive ECG recording, resulting in lower resting heart rates and small improvements in sensitivity of detection of drug-induced effects. Given the psychological benefits of group housing for NHPs, it is a refinement that should be considered when conducting ECG assessments in NHP toxicology studies.

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

INTRODUCTION: Parts A and B of the ICH S7 guidelines on safety pharmacology describe the in vivo studies that must be conducted prior to first time in man administration of any new pharmaceutical. ICH S7A requires a consideration of the sensitivity and reproducibility of the test systems used. This could encompass maintaining a dataset of historical pre-dose values, power analyses, as well as a demonstration of acceptable model sensitivity and robust pharmacological validation. During the process of outsourcing safety pharmacology studies to Charles River Laboratories, AstraZeneca set out to ensure that models were performed identically in each facility and saw this as an opportunity to review the inter-laboratory variability of these essential models. METHODS: The five in vivo studies outsourced were the conscious dog telemetry model for cardiovascular assessment, the rat whole body plethysmography model for respiratory assessment, the rat modified Irwin screen for central nervous system assessment, the rat charcoal meal study for gastrointestinal assessment and the rat metabolic cage study for assessment of renal function. Each study was validated with known reference compounds and data were compared across facilities. Statistical power was also calculated for each model. RESULTS: The results obtained indicated that each of the studies could be performed with comparable statistical power and could achieve a similar outcome, independent of facility. DISCUSSION: The consistency of results obtained from these models across multiple facilities was high thus providing confidence that the models can be run in different facilities and maintain compliance with ICH S7A and B.

Retinal folding in the term rabbit fetus-Developmental abnormality or fixation artifact?

UNLABELLED: Preclinical reproductive toxicology studies must be performed to provide information on the risk of causing fetal harm in pregnant patients. These studies detect fetal malformations, which may or may not be drug-related adverse events. In the rabbit fetus, "slight retinal folding" is commonly observed; there is anecdotal evidence that these folds may be caused by routine (Bouin's fluid) fixation. This study used magnetic resonance imaging (MRI) to assess rabbit retinal architecture in fresh specimens, which was then reassessed following Bouin's fluid fixation. A total of 30 fetuses from 5 litters were imaged. No retinal folding was detected in fresh specimens but it was observed in a majority of fetuses post-fixation. The use of Davidson's fixative followed by Bouin's fluid showed a markedly lower incidence of "slight retinal folding". CONCLUSION: slight retinal folds in the rabbit fetus are likely artifactual and can be reduced using Davidson's fixation prior to Bouin's.