Safety pharmacology aims to identify adverse effects of drugs prior to clinical trials through guidelines established by the ICH. The antihistamine terfenadine was found to cause a rare but lethal cardiac effect and highlighted the need for improved preclinical safety testing. Safety pharmacology studies objectives are to detect undesirable pharmacodynamic properties and adverse effects observed in toxicology and help inform decisions about beginning human testing. A variety of in vitro and ex vivo methods are recommended including isolated tissue and cell-based assays, and zebrafish and stem cell models to comprehensively evaluate a new drug's safety profile.

3. can be

4. • Safety pharmacology (SP):- Essential part of the drug
development process that aims to identify and predict adverse
effects prior to clinical trial

5. • In the mid 1990s the antihistamine, terfenadine given for mild
disease of hay fever – causing TdP- so - risk (death) clearly
outweighs benefit
• Predicting terfenadine's TdP risk was not possible by the
conventional preclinical toxicity testing methods conducted at the
time
• So studies were not able to detect the possibility of a rare lethal
event at therapeutic dosage
• Within 4 years, Safety Pharmacology evolved

6. Guidelines
SP studies are described in the International Conference on
Harmonisation (ICH) S7A and S7B guidelines
S7A - Approval by the Steering Committee under Step 2 and release for
public consultation
• 2 March 2000
S7B - Approval by the Steering Committee under Step 4 and
recommendation for adoption to the three ICH regulatory bodies.
• 8 November 2000

8. Objectives of Studies
1. Identify undesirable pharmacodynamic properties of a substance
that may have relevance to its human safety- To help protect
clinical trial participants and patients receiving trial drugs from
potential adverse effects
2. To evaluate adverse pharmacodynamic and/or pathophysiological
effects of a substance observed in toxicology and/or clinical
studies
3. To investigate the mechanism of the adverse pharmacodynamic
effects observed and/or suspected
4. Avoiding unnecessary use of animals and other resources

9. Objectives of Studies
5. Safety Pharmacology must conclude that a drug has a sufficiently
low potential to evoke adverse effects to be trialled in patients,
whereas discovery must conclude that a drug has a sufficiently
high potential for benefit to be trialled in patients
6. One of the key roles of Safety Pharmacology is to help inform the
decision to begin testing in humans

10. • Adverse clinical events
• A new patient population
• A new route of administration raises concerns not previously addressed

11. Interaction of preclinical scientific disciplines
and study models used to characterize the safety
profile of a new chemical entity

14. General Principle for SP
• The specific studies that should be conducted and their design will
vary based on individual properties and intended uses of the
pharmaceuticals
• Scientifically valid methods should be used (internationally
recognized)
• The use of new technologies and methodologies with sound
scientific principles is encouraged
• Safety pharmacology endpoints can be incorporated in the design
of toxicology, kinetic, clinical studies, etc.

15. • Although adverse effects of a substance may be detectable at
exposures that fall within the therapeutic range in appropriately
designed safety pharmacology studies, they may not be evident
from observations and measurements used to detect toxicity in
conventional animal toxicity studies
General Principle for SP

16. Considerations in Selection and Design
of Safety Pharmacology
Pharmacological effects vary depending on the specific properties of each
test substance, the studies should be selected and designed accordingly
The following factors should be considered:
1. Ligand binding or enzyme assay data suggesting a potential for adverse
effects
2. Results from previous safety pharmacology studies, from secondary
pharmacodynamic studies, from toxicology studies

17. 3. Effects related to the therapeutic class of the test substance, since
the mechanism of action may suggest specific adverse effects
e.g., proarrhythmia is a common feature of antiarrhythmic
agents.
4. Adverse effects associated with members of the chemical or
therapeutic class, but independent of the primary
pharmacodynamic effects e.g., anti-psychotics and QT
prolongation
Considerations in Selection and Design
of Safety Pharmacology

20. Ex vivo and in vitro systems
Can include, but are not limited to:
-Isolated Organs And Tissues
-Cell Cultures
-Cellular Fragments
-Subcellular Organelles
-Receptors
-Ion Channels
-Transporters And Enzymes

31. • hERG assay

34. • Zebrafish model:
(hESC-CM)
(hiPS-CM)
CVS

35. An overview of the multidisciplinary integration
required to evaluate the safety profile of a new
chemical entity (NCE) in Safety Pharmacology

36. Non-clinical methods recommended for use in
the safety pharmacology core battery of tests
by ICH Guidelines S7A and S7B

44. 1
Jeffrey Atkinson