Safety pharmacology studies for respiratory, CNS and CVS system

1. Presented by
Grandhi Sandeep Ganesh
Dept. of Pharmacology
1

2. PHARMACOLOGICAL PROFILING
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3. ADVERSE DRUG REACTIONS
TYPE TERM CHARACTERISTICS
A Augmented Dose dependent, frequent,
explained by
pharmacological drug
effect
B Bizarre Dose independent, rare,
unpredictable
C Chronic Dose and Time dependent
D Delayed Time dependent, rare
E End of treatment Time dependent, rare
https://www.futurelearn.com/courses/allergies/0/steps/68785 3

4. GUIDELINES
ICH S7A
Safety pharmacology
studies for human
pharmaceuticals
ICH S7B
The nonclinical evaluation
of the potential for delayed
ventricular repolarization
(QT interval prolongation)
by human pharmaceuticals
4https://www.ich.org/page/safety-guidelines

5. PHARMACOLOGY STUDIES
Primary
pharmacodynamic
studies
Safety
pharmacology
studies
Secondary
pharmacodynamic
studies
5https://www.ich.org/page/safety-guidelines

6. SAFETY PHARMACOLOGY
Safety pharmacology studies are
defined as those studies that investigate
the potential undesirable
pharmacodynamic effects of a
substance on physiological functions in
relation to exposure in the therapeutic
range and above
6https://www.ich.org/page/safety-guidelines

7. 7
Safety pharmacology
Core battery supplemental Follow-up
SAFETY PHARMACOLOGY
CNS CVS RESPIRATORY GIT RENAL
EMEA 2006

8. OBJECTIVES OF SAFETY PHARMACOLOGY
STUDIES
To identify undesirable pharmacodynamic properties of a substance that
may have relevance to its human safety
To evaluate adverse pharmacodynamic or pathophysiological effects of a
substance observed in toxicology studies
 To investigate the mechanism of the adverse pharmacodynamic effects
observed
8https://www.ema.europa.eu/en/documents/scientific-guideline/ich-s-7-safety-pharmacology-studies-human-pharmaceuticals-step-5_en.pdf
HAZARD IDENTIFICATION
RISK ASSESSMENT
RISK MANAGEMENT/MITIGATION

9. IMPORTANCE
Safety pharmacology issues have a significant impact on clinical
development attrition (both preclinical and during clinical development)
Data are important for Phase I dose-setting
Safety pharmacology studies are a regulatory requirement for IND
submissions prior to human exposure
The consequences of ‘getting it wrong’ can have dramatic implications
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Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

10. APPLICATIONS
Prevention of serious ADR in FIH studies
Understanding the concentration-response relationship for any effects on
major physiological systems that may be predictive of AE in man
In combination with other safety data, safety pharmacology should be used
to select the starting dose for FIH
Support mechanistic understanding of AE in clinical trials
10
Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

11. RESPIRATORY SAFETY PHARMACOLOGY
Respiratory Safety Pharmacology as
described in ICH S7A core battery aims
to evaluate the effects of a test substance
on pulmonary function
The basic procedure uses whole body
plethysmography.Several supplementary
and follow-up studies can be designed to
further evaluate the effects on respiratory
function
11
Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

12. RESPIRATORY SAFETY PHARMACOLOGY
CORE BATTERY STUDIES
Respiratory rate
tidal volume
hemoglobin oxygen saturation
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FOLLOW UP STUDIES
 airway resistance
 compliance
 pulmonary arterial pressure
 blood gases
 blood pH.
Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

13. 13
RESPIRATORY SAFETY PHARMACOLOGY
Evaluation of respiratory functions
Pumping efficiency Gaseous exchange
Function
Regulates gas exchange
between environment
and airways
Function
Regulates gas exchange
between airways and
blood
Components
Respiratory muscles
Components
Airways,alveoli,fibrous
network
Core measurements
Tidal volume,respiratory
rate,minute volume
Core measurements
Dynamic airway resistance
& lung compliance
Junnat H, Swaminathan S Safety pharmacology — Current and emerging concepts

14. RESPIRATORY RATE AND TIDAL VOLUME
Plethysmograph chambers
Head-out or head-enclosed volume displacement chambers
Face mask with Pneumotachometer
AIRWAY RESISTANCE & LUNG COMPLIANCE
Head out or head enclosed plethysmograph chambers
Facemask with Pneumotachometer
Pressure sensitive catheter
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RESPIRATORY SAFETY PHARMACOLOGY
Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

15. HEAD-OUT PLETHYSMOGRAPH CHAMBER
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Rat head-out chamber Dog head-out chamber
Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

16. PNEUMOTACHOGRAPH
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Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

17. FUNCTIONAL ENDPOINTS
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Inspiratory Time (Ti, ms)
Expiratory Time (Te, ms)
Peak Inspiratory Flow (PIF, ml/s)
Peak Expiratory Flow (PEF, ml/s)
Tidal Volume Vt (TV, ml)
Respiratory Rate (ResR, breaths/min)
Relaxation Time (Tr, ms)
Pause = (Te - Tr)/Tr
Minute volume (MV, ml/min) = (TV x ResR)
https://www.porsolt.com/contract-research_safety-pharmacology_core-battery-regulatory-package_respiratory-studies.phtml

18. PLEURALAND ARTERIAL PRESSURE
MEASUREMENTS
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Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

19. CNS SAFETY
PHARMACOLOGY
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20. CNS SAFETY PHARMACOLOGY
• Behaviour changes
• Locomotor activity
• Motor co ordination
• Sensorimoter reflexes:nociception body
temperature
CORE STUDIES
• Higher cognitive function
• Seizure liability
• Drug abuse and liability
• Ligand specific binding
FOLLOW UP STUIES
20Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

21. APPROACHES TO STUDY ADR’S
INVITRO STUDIES
Neuronal cultures
Invitro electrophysioslogy(Ion channels,neurons,slices)
INVIVO STUDIES
Behavioral
Neurophysiology recordings(EEG,ERG,EMG,NERVE CONDUCTION
VELOCITY)
Neuro chemical (invivo microdialysis,biomarkers)
Neuroimaging (MRI)
Post mortem (neurohistopathology)
21Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

22. INVITRO VS INVIVO
 Mainly use invivo methods in conscious animals ,reason is cns
function is best evaluated in intact and freely moving animals
ETHICALAND ANIMAL WELFARE ISSUES
 As procedures involving living animals, important considerations
in the choice of method ,to avoid stressful procedure as much as
possible
In field of safety pharmacology, aim is to assess the risk of
inducing unwanted effects, the possibility of causing animal
distress is high than in other areas of pharmacology
The experimenter must therefore maintain awareness of issues, not
only planning and revising the protocols but also during the
experiment
22Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

23. CNS CORE BATTERY STUDIES
General behavioural signs (Irwin test)
Spontaneous locomotion (activity meter test)
Neuromuscular coordination (Rotarod test)
Convulsive threshold (Electro convulsive shock)
Interaction with hypnotics (Barbital interaction test)
Effects on pain threshold (Hot plate test)
Others-tail flick method, morris water maze, passive avoidance
23Junnat Hamdama Safety pharmacology Current and emerging concepts

24. IRWIN TEST
This method is to evaluate the qualitative effect of test substance
on behavioural and physiological functions and also duration of
action
The parameters observed are
AUTONOMIC
EFFECTS
SENSORIMOTOR
EFFECTS
NEUROMUSCULAR
EFFECTS
BEHAVIOURAL
EFFECTS
Salivation Touch response Posture Arousal
Lacrimisation Palpebral reflex Grip strength Vocalisation
Pilorection Startle reflex Tremor Aggressiveness
Rectal temperature Pinna reflex Traction response Sniffing
Abnormal urination,
defecation, respiration
Writhing reflex Twitches Grooming
24Will Redfern Safety Pharmacology of the Nervous System

25. IRWIN TEST
Conclusion
This test provide a rapid detection of test substances toxicity, active
dosage range Effects on behavioural and physiological function
Modification:
Functional Observation Battery(FOB)
25Will Redfern Safety Pharmacology of the Nervous System

26. ACTIVITY METER TEST
It is a automated apparatus with large no.of animals,less labour ,more
precise statistical analysis
The quantitative data obtained enable the generation of dose response
curve and more precise estimation of MED and ED50
EVALUATION
Rearing movements and locomotion
Comparision of single photo beam interruptions with paired
interruptions
The data is usually analysed by students T test
26Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

27. Critical assesment
This test estimate whether the test substance possess
psychostimulant or sedative activity
Modifications to method
Interrupting of photo electric beams
Activity wheels
Changes in electromagnetic fields
Doppler effects
Video image analysis
Telemetry
Detections of vibrations generated by animals
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ACTIVITY METER TEST
Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

28. SUPPLEMENTAL STUDIES
Automated video systems
Integrated video systems
EEG
Telemetry
In vitro hippocampal brain slice assay
28Junnat Hamdama Safety pharmacology Current and emerging conceptsVincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

29. OFF TARGETS
TARGET MAJOR ORGAN
SYSTEM
EFFECTS
Acetycholinesterase CNS Muscle paralysis
Dopamine receptors CNS Depression,dystonia
GABA a receptor CNS Ataxia,muscle relaxation
M1 CNS Vagal effects
Nicotine receptor CNS Nausea,sweating,tremors
Noradrenaline receptor CNS Locomotor activity
Mu receptor CNS Hypothermia,sedation
Kappa receptor CNS Dysphoria,confusion
Delta receptors CNS Psychometric effects
5HT 1A CNS Reduced REM sleep
5HT 1B CNS Cerebral constriction
5HT 2A CNS Hallucinations
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30. STATISTICALANALYSIS
TYPE I ERRORS:
false positive errors
TYPE 2 ERRORS:
false negative errors
type 2 errors should be decreased as much possible, even if there is increase
risk of type 1 errors
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31. CVS SAFETY
PHARMACOLOGY
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32. SAFETY PHARMACOLOGY
In the last few decades, a large number
of drugs have been withdrawn from the
market due to adverse cardiovascular
system (CVS) effects, which were
responsible for 45% of post-approval
withdrawals
It is important to note that QT
prolongation has resulted in one third of
all drug withdrawals between 1990 and
2006 due to the risk of developing fatal
arrhythmias.
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33. GUIDELINES
ICH S7B
• The non clinical evalutation of the potential
for delayed ventricular repolarization (QT
interval prolongation) by human
pharmaceuticals
QT interval prolongation by
terfenadine has led to implementation
of ICH S7B
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34. CARDIOVASCULAR SYSTEM ASSESSMENT
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35. PARAMETERS
Arterial Blood Pressure (ABP, mmHg)
Left Ventricular Pressure (mmHg)
Heart Rate (HR, bpm)
PR interval (ms)
QRS interval (ms)
QT and corrected QT
https://www.porsolt.com/contract-research_safety-pharmacology_core-battery-regulatory-package_in-vivo-cardiovascular-studies.phtml
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36. • hERG ( human Ether-à-go-go-
Related Gene) is a gene
(KCNH2) that codes for a protein
known as Kv11.1 the
alpha subunit of a potassium ion
channel
• the hERG channel mediates the
repolarizing IKr (inward rectifier
potassium current) current in
the cardiac action potential,
which helps coordinate the heart's
beating
HERG ASSAY
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37. HERG ASSAY
There is considerable focus on the promiscuous hERG channel, which
mediates an inward current, that, when blocked, slows myocardial
repolarisation associated with prolongation of the QT interval in the
ECG. This prolongation lengthens the duration of the cardiac action
which appears to be a critical contributing factor in the development
of a fatal arrthymia: Torsades de Pointes
The effects of an NCE on the hERG channel can be detected using
screening methodologies such as radio-labelled ligand binding and
automated voltage clamp assays.
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38. TELEMETRY
The telemetry device consists of
 the implantable transmitter, which measures the pressure. This
device contains a highly stable, ion implant, semiconductor, strain-
gauge sensor and Arterial pressure is transmitted to the sensor via a
0.7-mm diameter, fluid filled catheter;
 the receiver which detects the signal from the implanted transmitter
and converts it to a form readable by computer;
 the pressure reference module, which measures atmospheric
pressure to allow for the telemetered absolute pressure to be
converted to a gauge pressure;
 the data acquisition software, which accepts data from the reference
module and the receivers
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39. OFF TARGETS
Target Major organ system Effect(s)
Acetylcholinesterase Cardio vascular CV collapse
Adenosine A1 receptor Cardio vascular Bradycardia, AV block
Calcium channel Cardio vascular Hypotension
Dopamine D1 receptor Cardio vascular Hypotension
Histamine H1 receptor Cardio vascular Histamine H1 receptor
Muscarinic M1 receptor Cardio vascular Vagal effects, blood pressure
changes,
Phosphodiesterase 3A Cardio vascular Increase heart rate
Potassium channel hERG Cardio vascular QT prolongation
Potassium channel KCNQ1 Cardio vascular Hypotension
Sodium channel Cardio vascular Prolonged QRS interval,
B.H. Morimoto et al. Safety Pharmacology in Drug Discovery and Development
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