Guozhen Xing1, Jing Lu1, Miaomiao Hu1, Shaodong Wang1, Li Zhao1, Weijun Zheng1, Jason Schofield2, Karen Oldman3, Debbie Adkins3, Hong Yu1, Stefan Platz2, Jin Ren4, Matthew Skinner5. 1. Center for Drug Safety Evaluation and Research (CDSER), State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Haike Road 501, Shanghai 201203, China. 2. Department of Safety and Metabolism, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom. 3. Discovery Sciences - Statistics, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom. 4. Center for Drug Safety Evaluation and Research (CDSER), State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Haike Road 501, Shanghai 201203, China. Electronic address: jren@cdser.simm.ac.cn. 5. Department of Safety and Metabolism, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom. Electronic address: matthew.skinner@astrazeneca.com.
Abstract
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.
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.
Authors: Helen Prior; Anna Bottomley; Pascal Champéroux; Jason Cordes; Eric Delpy; Noel Dybdal; Nick Edmunds; Mike Engwall; Mike Foley; Michael Hoffmann; Robert Kaiser; Ken Meecham; Stéphane Milano; Aileen Milne; Rick Nelson; Brian Roche; Jean-Pierre Valentin; Gemma Ward; Kathryn Chapman Journal: J Pharmacol Toxicol Methods Date: 2016-03-31 Impact factor: 1.950