SAFETY PHARMACOLOGY: CARDIOVASCULAR TELEMETRY. Aileen Milne PhD, Manager, Safety Pharmacology

Transcription

1 SAFETY PHARMACOLOGY: CARDIOVASCULAR TELEMETRY Aileen Milne PhD, Manager, Safety Pharmacology

2 SAFETY PHARMACOLOGY SERVICES OVERVIEW Full Range of S7A and S7B studies herg assay Respiratory function plethysmography(rat/mouse) CNS function Irwin screen (rat/mouse) Cardiovascular function Implanted telemetry (rat/ferret/dog/nhp/mini pig/guinea pig) S6 and S9 studies Inclusion of safety pharmacology endpoints in repeat dose toxicology studies Supplemental Studies Tier II assessments and supplemental studies tailored to meet specific project needs Tier II: Cardiovascular system, respiratory system and central nervous system Renal / Urinary Gastrointestinal Functional investigations in anesthetized animals (mainly cardiovascular and pulmonary) 2 EVERY STEP OF THE WAY

3 SAFETY PHARMACOLOGY CARDIOVASCULAR TELEMETRY Implantable and jacketed external telemetry (JET) Continuous measurement of CV parameters in unrestrained animals Implantable telemetry Various implant types for continuous measurement of ECG, BP, LVP L series, long battery life, can be refurbished, suitable for long term colonies M series, designed for tox studies, minimally invasive, shorter battery life, disposable Jacketed external telemetry (JET) Non invasive, continuous assessment of ECG Combination of JET and implantable telemetry (for ECG and BP) Using minimally invasive BP implants which transmit to the jacket 3 EVERY STEP OF THE WAY

4 Implanted telemetry for safety pharmacology studies

5 SAFETY PHARMACOLOGY CARDIOVASCULAR TELEMETRY Dog/ primate/ mini-pig implantable telemetry Dedicated telemetry suites with latest digital technology Animals socially housed during telemetry recordings Inclusion of LVP measurement for assessment of contractility Colonies of instrumented animals available for quick study starts Experienced in administration via inhaled route or i.v. infusion Validated with reference agents 5 EVERY STEP OF THE WAY

6 SAFETY PHARMACOLOGY CARDIOVASCULAR TELEMETRY Implantable telemetry 6 EVERY STEP OF THE WAY

7 IMPLANTABLE TELEMETRY IN MINIPIGS MOXIFLOXACIN Dosed by oral gavage, n=5 QTca interval: group mean ± sem Heart rate: group mean ± sem QTca interval ms Heart rate bpm mg/kg Moxifloxacin 10 mg/kg Moxifloxacin 30 mg/kg Moxifloxacin 100 mg/kg Moxifloxacin 1st Feed: -3 h 2nd Feed 1st Feed: -3 h 2nd Feed Time (hours) 7 EVERY STEP OF THE WAY

8 EFFECT OF SALBUTAMOL OR L-NAME ON MEAN ARTERIAL BLOOD PRESSURE IN TELEMETERED RATS 8 EVERY STEP OF THE WAY

9 CARDIOVASCULAR TELEMETRY IN SAFETY PHARMACOLOGY Study Design Considerations for stand alone telemetry studies (S7A/B) Ascending dose versus cross over design wash out period route of administration expected clinical signs Housing any reason not to socially house? Sampling for bioanalysis consider frequency and timing Timing of Feeding especially important for minipigs Duration of recording especially for long acting compounds 9 EVERY STEP OF THE WAY

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11 CV Telemetry in repeat dose toxicology studies

12 CARDIOVASCULAR TELEMETRY IN REPEAT DOSE TOXICOLOGY STUDIES Dog/ primate/ minipig jacketed telemetry Allows continuous, undisturbed assessment of ECG Animals socially housed during telemetry recordings Blood pressure measurements using minimally invasive telemetry device in conjunction with jackets (dogs) Validated with reference agents 12 EVERY STEP OF THE WAY

13 13 EVERY STEP OF THE WAY CARDIOVASCULAR TELEMETRY IN REPEAT DOSE TOXICOLOGY STUDIES

14 JET VALIDATION IN PRIMATES - MOXIFLOXACIN Dosed by oral gavage n=5m QTca interval: group mean ± sem Heart rate: group mean ± sem QTc Interval (ms) Heart rate (bpm) mg/kg - Moxifloxacin 30 mg/kg - Moxifloxacin 100 mg/kg - Moxifloxacin Time (hours) 14 EVERY STEP OF THE WAY

15 CARDIOVASCULAR ASSESSMENT JACKETED EXTERNAL TELEMETRY No disturbance to social groups minimises stress 15 EVERY STEP OF THE WAY

16 CARDIOVASCULAR ASSESSMENT JACKETED EXTERNAL TELEMETRY 16 EVERY STEP OF THE WAY

17 ASSESSMENT OF ECG AND BLOOD PRESSURE PARAMETERS IN REPEAT DOSE TOXICOLOGY STUDIES Minimally invasive telemetry devices can be used in conjunction with jacketed external telemetry Telemetry device is small and relatively cheap Short transmission range, receiver is housed in a pocket in the jacket, positioned over the implant site Technique validated in dogs and presented at Eurotox in EVERY STEP OF THE WAY

18 ASSESSMENT OF ECG AND BLOOD PRESSURE PARAMETERS IN REPEAT DOSE TOXICOLOGY STUDIES M series telemetry device In NHP, due to range of movement and behaviour exhibited by the animals, signal drop out and cross talk can occur The jacketing procedure is especially stressful for NHP Charles River performed beta testing on a new DSI telemetry device M series implant designed for use in toxicology studies Disposable device Long transmission range, no jackets required Minimally invasive surgery Battery life of 35 days Relatively cheap 18 EVERY STEP OF THE WAY

19 CARDIOVASCULAR TELEMETRY IN REPEAT DOSE TOXICOLOGY STUDIES M-series telemetry implants for measurement of ECG and BP Suitable for use on studies of 13 weeks duration Possible welfare benefits over (JET/MIBP), especially for primates Reduced stressed by elimination of jacketing procedure Mean arterial pressure mmhg mg/kg L-NAME 0.1 mg/kg L-NAME 1 mg/kg L-NAME 10 mg/kg L-NAME QTca interval ms mg/kg Moxifloxacin mg/kg Moxifloxacin 40 Predose Predose EVERY STEP OF THE WAY Time (hours)

20 THE M-SERIES TELEMETRY DEVICE MAP and HR over study duration Mean arterial pressure mmhg Predose Time Post Treatment (Hours) Day -4 Day 36 Day 39 Day 43 Day 46 Day 50 Day 53 Day 57 Day 60 Day 64 Day 67 Heart rate bpm Predose Time Post Treatment (Hours) 20 EVERY STEP OF THE WAY

21 21 EVERY STEP OF THE WAY THE M-SERIES TELEMETRY DEVICE

22 THE M-SERIES TELEMETRY DEVICE Summary Allows high quality ECG and BP data acquisition without the need for jacketing Refinement for NHP where there is a requirement for both ECG and BP data Removes the stress of the jacketing procedure Implants are suitable for use beyond 17 weeks Advantage of fixed ECG leads Data are comparable with traditional telemetry Potential reduction in animal use, as high quality CV evaluation in repeat dose toxicology studies can replace stand alone telemetry study 22 EVERY STEP OF THE WAY

23 CARDIOVASCULAR TELEMETRY - M-SERIES TELEMETRY DEVICE Collection of high quality CV data without the need for jacketing 23 EVERY STEP OF THE WAY

24 STATISTICAL ANALYSIS OF CARDIOVASCULAR DATA COLLECTED ON A REPEAT DOSE STUDY Parallel treatment groups with M and F animals Pool data from M and F animals where possible Repeated measures ANCOVA (pre dose measurement included in the model as a covariate) Repeated measures ANOVA M11 Implant Parameter ANCOVA ANOVA ANCOVA ANOVA n=6 n=8 n=6 n=8 n=6 n=8 n=6 n=8 SBP, mmhg DBP, mmhg MAP, mmhg HR*, bpm PR interval, ms QRS interval, ms QTca, ms QT interval, ms RR interval, ms Body Temperature, C *HR is derived from BP (M11 implant) or from ECG (JET). JET 24 EVERY STEP OF THE WAY

25 CARDIOVASCULAR TELEMETRY IN REPEAT DOSE STUDIES Study Design Considerations Lead time allow time for surgical recovery if implants are required (2 weeks) Acclimation acclimation to jackets and/or other study procedures that affect telemetry phase is essential Timing of telemetry recordings Day 1 not usually an option due to other study activities Consider an acute phase if Day 1 data is essential duration of recordings frequency of recording, include recovery period? Data analysis and statistics group sizes pooling of M and F data for statistical analysis use bioanalysis data to help inform analysis of recovery data may not be required 25 EVERY STEP OF THE WAY

26 CARDIOVASCULAR TELEMETRY- SUMMARY Cardiovascular telemetry provides high quality, continuous CV data from socially housed animals in their home pen Inclusion of CV telemetry in toxicology studies provides valuable data in a repeat dose setting Generally; S7A/B stand alone CV study for compounds with CV liability, include CV telemetry in repeat dose tox study as well S6 or S9 include CV telemetry in repeat dose tox study however, a stand alone study may be warranted 26 EVERY STEP OF THE WAY

27 CARDIOVASCULAR TELEMETRY IN NON RODENTS Social housing 27 EVERY STEP OF THE WAY

28 Questions?

29 ECG ANALYSIS Ponemah ECG Pro module for template analysis Raw data (1 min) Template Library Window Continuous ECG recording 29 EVERY STEP OF THE WAY

30 IMPLANTABLE TELEMETRY IN DOGS MOXIFLOXACIN Dosed by oral gavage, n=4 QTca interval: group mean ± sem Heart rate: group mean ± sem QTca interval ms Heart rate beats/min mg/kg - Moxifloxacin 10 mg/kg - Moxifloxacin 30 mg/kg - Moxifloxacin 90 mg/kg - Moxifloxacin Time (hours) 30 EVERY STEP OF THE WAY

31 IMPLANTABLE TELEMETRY IN PRIMATES - MOXIFLOXACIN Dosed by oral gavage, n=5 QTca interval: group mean ± sem Heart rate: group mean ± sem QTca interval ms Predose Heart rate bpm mg/kg - Moxifloxacin 10 mg/kg - Moxifloxacin 30 mg/kg - Moxifloxacin 100 mg/kg - Moxifloxacin 80 Predose Time (hours) 31 EVERY STEP OF THE WAY

32 JET VALIDATION IN MINIPIGS - MOXIFLOXACIN Dosed by oral gavage n= 3F + 2M QTca interval: group mean ± sem Heart rate: group mean ± sem QTca interval ms Predose feed Heart rate bpm 0 mg/kg - Vehicle mg/kg - Moxifloxacin 30 mg/kg - Moxifloxacin mg/kg - Moxifloxacin Predose feed Time (hours) 32 EVERY STEP OF THE WAY

33 CARDIOVASCULAR ASSESSMENT JACKETED EXTERNAL TELEMETRY Acclimation to jackets HR data 33 EVERY STEP OF THE WAY