Safety Pharmacology Tier 1 Study

1. SAFETY
PHARMACOLOGY
TIER 1
Prepared By :
Savan Chhatrola
( 22SOPCL21001 )
Guidence By :
Udit Trivedi
( Assi. Professor )

2. Content List
1
2
3
4
6
7
8
12
1
5
17

3. ICH Deifinition for Safety Pharmacology
'Safety Pharmacology Study are those studies that investigate
potential undesirable Pharmacodynamic effect of a substance on
physiological function in relaxation to exposure therapeutics range
and above.
ICH S7A Guidelines for Safety Pharmacological Studdy ( 2000 )
"Docis sola facit venenum nen sit" - The dose makes the poison
- Paracelsus ( 1494 - 1541 )
1
01

4. Objectives
02
• To identify undesirable pharmacodynamic properties of a
substance that may have relevance to its human safety.
• To evaluate adverse pharmacodynamic and/or
pathophysiological effects of a substance observed in
toxicology and/or clinical studies.
• To investigate mechanisms of adverse pharmacodynamic
effects observed and/or suspected
2

5. Reason for attrition during devlopment
03
• Safety still main reasson for drug
dicontinuation
• Situation didn't improve through the 90s
• CV Safety is the most common target organ
Landis and Cola, 2004
3

6. Safety reason for drug withdrawal
04
• Cardiovascular and CNS toxicities have
been the leading reasons for drug
withrawals over the last decade
• Strategies to reduce predictable toxicities
are central to improving the qaulities and
viability of new therapeutic agents
Mamoshina, Polina & Rodriguez, Blanca & Bueno-Orovio,
Alfonso. (2021)
4

7. 5

8. Scope of Studies
05
• Core Battery Studies
Investigate the effect of the test substance on vital functions
Cardiovascular, Respiratory and Central Nervous System
• Follow up studies
Provide greater depth of understanding than, or additional knowledge to, that
provided by the core battery on vital functions
• Supplemental studies
Evaluate potential adverse pharmacodynamic effects on organ system function
not addressed by the core battery or repeated dose toxicity studies
6

9. What is typically measured as the core battery ?
06
1. Central Nervous System
2. Cardiovascular System
3. Respiratory System
Motor activity, Behavioural changes, Coordination, Sensory/motor reflex
responses, Body Temperature (e.g. using FOB).
blood pressure, heart rate, ECG; In vivo, in vitro and/or ex vivo methods incl. methods for
repolarization and conductance abnormalities should also be considered.
respiratory rate and tidal volume or hemoglobin oxygen saturation. Clinical
observation of animals is generally not adequate.
7

10. Central Nervous System
07
In Core Battery
• Motor Activity
• Behavioural Changes
• Coordination
• Sensory/Motor Reflex Response
• Body Temperature
In Follow Up Studies
• Learning And Memory
• Ligand Specific Binding
• Neurochemistry
• Visual & Auditory Examination
8

11. Evaluation Method
• Functional Observation Battery ( FOB )
• Modified Irwin's Test
FOB
Neurotoxicological and
Neuropathological Investigation
9

12. Ptosis
Myosis/Mydriasis
Salivation
Lacrimation
Convulsion
Tremors
Jumping
Aggression
Head-Twitches
Chewing
Sniffing
Scratching
Moto
r
Catalepsy
Akinesi
Irwin's Test
Rats or mice are administered the test substance and then observed for the next several hours and
on the following day. Clinical signs are grouped into several categories in an attempt to highlight
the particular characteristics of the test substance, as follows:
Excitation Stereotype
Sedation
Pain
Autonomic
Other Measure
Writhing
Analgesia
Decrease Activity Increase/Decrease Respiration
Hyperthermia/Hypothermia
10

13. Other Established Techniques
• Rotarod
• Hot Plate Test, Tail flick, Paw Pressure
• Photoelectric beam interruption technique
• Passive Avoidance Tests
• Pentylenetetrazol ( PTZ ) seizure tests
• Electroencephalography ( EEG )
11

14. Cardiovascular System
08
In Core Battery
• Blood Pressure
• Heart Rate
In Follow Up Studies
• Cardiac Output
• Ventricular Contractility
• Vascular Resistance
• Endogenous Exogenous
Substances on the
cardiovascular response
1

15. Evaluation Method
• Electrocardiogram
• Establish Technique in vitro - hERG Assay
⚬ The effect of an NCE on the hERG Channel can be detected using screeninng methodologies such
as
• Manual patch clamp
• Automated high throughput patch clamp
• Isolated organ Preparation
• Whole Heart Prreparation
• Isolation Perkinje Fibres
1

16. hERG Assay ( human Ether-a-go-go Related Gene )
The alpha subunit of a potassium ion channels in the heart that codes for protein known as K,11.1
Ion channel protein ( the rapid delayed rectifier current ) that conducts potassium ions out of the
muscle cells of heart.
Inhibition of hERG current causes QT interval prolongatiom resulting in potentially fatal
ventricular tachyarrythemia called Torsade de Pointes.
1

17. Respiratory Sytem
09
In Core Battery
• Respiratory rate
• Tidal Volume
• Haemoglobin Oxygen Saturation
In Follow Up Studies
• Airway Resistance
• Compliance
• Pulmonary Arterial Pressure
• Blood Gases
• Blood pH
15

18. Evaluation Method
• Plethysmography
• Head out Plethysmography
• Whole Body Plethysmography
Respiratory Parameter
• Inspiratory Time (Ti, ms )
• Expiratory Time (Te, ms )
• Peak Inspiratory Flow ( PIF, m/s )
• Peak Expiratory Flow ( PEF, m/s )
• Tidal Volume ( Tv, ml )
• Respiratory Rate ( ResR, breaths/min )
• Relaxation Time ( Tr, ms )
1

19. References
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[1] Ich official web site. ICH. (n.d.). https://www.ich.org/page/safety-guidelines
1
[2] Kola, I., Landis, J. Can the pharmaceutical industry reduce attrition rates. Nat Rev
Drug Discov 3, 711–716 (2004). httpsdoi.org10.1038nrd1470
[3] Mamoshina, Polina & Rodriguez, Blanca & Bueno-Orovio, Alfonso. (2021). Toward a
broader view of mechanisms of drug cardiotoxicity. Cell Reports Medicine. 2. 100216.
10.1016j.xcrm.2021.100216.
[4] Bass A et al. (2004) Origins, practices and future of safety pharmacology. J Pharmacol
Toxicol Methods 49, 145-51.
[5] Fermini B & Fossa AA (2003) The impact of drug-induced QT interval prolongation
on drug discovery and development. Nature Reviews: Drug Discovery. 2, 439-47.

20. References
10
[6] Redfern WS et al. (2002) Safety pharmacology - a progressive approach. Fund. Clin.
Pharmacol. 16, 161-173.
18
[7] https://www.vivotecnia.com/safety-pharmacology/
[8] Chandel, Saket & Patel, Pushpendra & Sahu, Jyoti. (2017). A Detailed Review on
Nociceptive Models for the Screening of Analgesic Activity in Experimental Animals.
10.11648/j.ijnpt.20160206.11.
[9] https://www.criver.com/products-services/discovery-services/pharmacology
studies/neuroscience-models-assays/neuroscience-methods endpoints/electrophysiology/patch-
clamp?region=3701

21. THANK
YOU!