Nanded Pharmacy College, Nanded

1. Presented By: Guided By:
Sourabh G. Atak Ms. S. A. Farooqui
M.Pharm 1st yr Department of Pharmacology
NANDED PHARMACY COLLEGE, NANDED
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2.  OBJECTIVES OF SAFETY PHARMACOLOGY.
 PRINCIPLE
 SAFETY PHARMACOLOGY
 GENERAL CONSIDERATIONS IN SELECTION
 TEST SYSTEM
 USE IN IN VIVO & IN VITRO STUDIES
 EXPERIMENTAL DESIGN
 SAFETY PHARMACOLOGY CORE BATTERY
 REFERENCES.
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3.  To help protect clinical trial participants and patients
receiving marketed products from potential adverse effects
of pharmaceuticals
 Avoiding unnecessary use of animals and other resources.
 SCOPE:-
 Applies to new chemical entities and biotechnology-derived
products.
 Applied to marketed pharmaceuticals when appropriate
(e.g., when adverse clinical events, a new patient population, or a
new route of administration raises concerns not previously
addressed).
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4.  The specific studies that should be conducted and their design
will vary based on the 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.
 Should be evaluated in specific safety pharmacology studies.
 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.
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5.  The studies that investigate the potential undesirable
pharmacodynamic effects of a substance on Safety
Pharmacology Studies for Human Pharmaceuticals
physiological functions in relation to exposure in the
therapeutic range.
Three categories:
 Primary pharmacodynamic,
 Secondary pharmacodynamic
 Safety pharmacology studies.
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6.  Mechanism of action may suggest specific adverse effects
e.g., proarrhythmia is a common feature of antiarrhythmic
agents.
 Primary pharmacodynamics effects e.g., anti-psychotics and
QT prolongation.
 Ligand binding or enzyme assay data suggesting a potential
for adverse effects.
 Results from previous safety pharmacology studies, from
secondary pharmacodynamics studies, from toxicology
studies.
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7. General consideration on test system :
 General consideration on selection of animal model should include:-
 pharmacokinetic profile
 species
 strain
 gender
 age
 the susceptibility
 sensitivity
 reproducibility of the test system and available background data
on the substance.
 The time point for the measurement of human should
be based on :-
 Pharmacokinetic factor
 Pharmacodynamics factor
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8. Animal models as well as ex vivo and in vitro
preparations can be used as test systems.
Ex vivo and in vitro systems can include :
 isolated organs and tissues
 cell cultures
 cell organelles
 subcellular organelles etc.
 In vivo animal include :
 unanaesthetized animals
 Data from unrestrained animals used for telemetry.
 For unanesthetized animals, the avoidance of
discomfort or pain is a foremost consideration.
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9. Sample size & Use of Controls:
 Size of the groups :- should be sufficient to allow
meaningful scientific interpretation.
 No. of animal should be adequate.
 Negative and positive control groups should be included ;
positive group may not be necessary.
 Exclusion of controls from studies should be justified.
Route of Administration :-
 Clinical route of administration should be used .
 Exposure to the parent substance and its major metabolites
should be similar to that achieved in humans.
 If clinical use involves multiple routes, consider more than
one route.
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10. Dose Levels or Concentrations of Test
Substance:
(A) In Vivo Studies-
 toxic range (e.g., tremors or fasciculation during ECG
recording) may confound the interpretation of the results
and may also limit dose levels.
 Dose that produce moderate adverse effects in this study
similar route & duration.
 These adverse effects can include dose-limiting
pharmacodynamics effects or other toxicity.
 Testing of a single group may be sufficient.
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11. (B) In Vitro Studies-
 To establish a Concentration-effect relationship.
 The range of concentrations selected - detect an effect
on the test system.
 This range may influence physico- chemical properties
of the test substance and other assay specific factors.
 In the absence of an effect, the range of concentrations
selected should be justified.
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12. 1.Central Nervous System
In core battery In follow up studies
 Motor activity learning and memory
 Behavioural changes ligand-specific binding
 Coordination Neurochemistry
 Sensory/motor reflex response Visual & auditory
examination
 Body temperature
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13. Evaluation methods
 Established techniques
 Rota rod
 Hot plate test, Tail flick, paw
pressure
 photoelectric beam interruption
techniques
 passive avoidance tests
 Pentylenetetrazol (PTZ) seizure
tests
 Electroencephalography (EEG)
 Emerging techniques
 Automated video systems
 Integrated video and EEG
systems
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14. 2. Cardiovascular system (CVS)
Core battery Follow up studies
 Blood pressure Cardiac output
 Heart rate Ventricular contractility
 Vascular resistance
 Endogenous & exogenous substances
 On the cardiovascular responses
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15. Evaluation methods
Electrocardiogram (ECG)
Established techniques
(In vitro hERG assay)
 Manual patch clamp
 Automated high-throughput patch
clamp
 Isolated organ preparation
 Whole heart preparation
 Isolated purkinje fibres
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16. 3.Respiratory system
Core battery Follow up studies
 Respiratory rate Airway resistance
 Tidal volume compliance
 Haemoglobin oxygen saturation
 pulmonary arterial pressure
 blood gases
 blood pH.
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17. Evaluation methods
 Plethysmography
 Head out Plethysmography
 whole body plethysmography
 Respiratory parameters-
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18.  ICH Harmonized Tripartite Guideline (M3) “Timing of Non-
clinical Safety Studies for the Conduct of Human Clinical
Trials for Pharmaceuticals” (1997)
 ICH Harmonized Tripartite Guideline (S6) “Preclinical Safety
Evaluation of Biotechnology-derived Pharmaceuticals” (1997).
 Mattsson, J. L., Spencer, P. J. and Albee, R. R.: A performance
standard for clinical and Functional Observational Battery
examinations of rats. J. Am. Coll. Toxicol. 15, 239 (1996).
 Irwin, S.: Comprehensive observational assessment: 1a. A
systematic, quantitative procedure for assessing the behavioural
and physiologic state of the mouse. Psychopharmacologia
(Berl.) 13, 222-257(1968).
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