The document discusses safety pharmacology studies that are conducted to evaluate potential adverse effects of pharmaceutical substances on vital organ systems. It describes the safety pharmacology core battery that investigates effects on the central nervous, cardiovascular and respiratory systems. Follow up studies provide more in-depth understanding of effects on these systems. Supplemental studies evaluate effects on other organ systems like renal, gastrointestinal and immune systems. A variety of evaluation methods are used like functional observation, electrocardiography, plethysmography and biomarkers. Conditions where safety pharmacology studies may not be needed are also outlined.

1. K.SHIRISHA
170117887005
G. Pulla Reddy College of Pharmacy
13/7/2018

2. I Safety Pharmacology Core Battery
 Safety pharmacology core battery is to investigate the effects of the test
substance on vital functions.
 Central Nervous System
 Cardiovascular System tier 1
 Respiratory System
Follow-up Studies For Safety Pharmacology Core Battery
 These are meant to provide a greater depth of understanding than, or
additional knowledge to, that provided by the core battery on vital
functions for potential adverse pharmacodynamic effects

3. II Supplemental Safety Pharmacology Studies
 To evaluate potential adverse pharmacodynamic effects on organ
system functions not addressed by the core battery or repeated dose
toxicity studies
 Renal/Urinary System tier 2
 Gastrointestinal System
 Other Organ Systems Skeletal system
Immune & endocrine functions

4. I Safety Pharmacology Core Battery
1. Central Nervous System
In core battery In follow up studies
 Motor activity learning and memory
 Behavioral changes ligand-specific binding
 Coordination Neurochemistry
 Sensory/motor reflex response Visual & auditory examination
 Body temperature

5. Evaluation methods
 Functional observation Battery (FOB)
 Modified Irwin's test
FOB
neurotoxicological and
neuropathological investigations

6. Other established techniques
 Rotarod
 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

7. 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

8. Evaluation methods
 Electrocardiogram (ECG)
Established techniques
In vitro
hERG assay
The effects of an NCE on the hERG channel can be detected using
screening methodologies such as
 Manual patch clamp
 Automated high-throughput patch clamp
 Isolated organ preparation
 Whole heart preparation
 Isolated purkinje fibres

9. hERG assay (human Ether-a-go-go Related Gene)
 The alpha subunit of a potassium ion channels in the heart that codes for a
protein known as Kv11.1
 ion channel proteins (the 'rapid' delayed rectifier current (IKr)) that conducts
potassium (K+) ions out of the muscle cells of the heart
 Inhibition of the hERG current causes QT interval prolongation resulting in
potentially fatal ventricular tachyarrhythmia called Torsade de Pointes.

10. 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.

11. Evaluation methods
 Plethysmography
 Head out Plethysmography
 whole body plethysmography
 Respiratory parameters:
 Inspiratory Time (Ti, ms)
 Expiratory Time (Te, ms)
 Peak Inspiratory Flow (PIF, ml/s)
 Peak Expiratory Flow (PEF, ml/s)
 Tidal Volume (TV, ml)
 Respiratory Rate (ResR, breaths/min)
 Relaxation Time (Tr, ms)

12. II Supplemental Safety Pharmacology Studies
1.Renal/Urinary System
Renal parameters should be assessed are
 Urinary volume,
 specific gravity,
 osmolality,
 pH, fluid/electrolyte balance,
 proteins, cytology, and
 blood chemistry determinations such as blood urea nitrogen, Na+,
Cl-, K+, creatinine and plasma proteins

13. Kidney injury markers
Functional markers leakage markers
 urinary glucose aspartate aminotransferase (AST),
 Protein alanine amino- transferase (ALT),
 Albumin lactate dehydrogenase (LDH),
 Calcium α-glutamyl transferase (GGT),
 alkaline phosphatase (ALP)
 N-acetyl-α-D-glucosaminidase (α-NAG)
 new kidney injury molecule-1 (KIM-1) and
 markers Clusterin (CLU)
 These kidney injuries are assessed primarily using histology

14. 2. Gastrointestinal System
 Gastric secretion
 Gastrointestinal injury potential
 Bile secretion
 Transit time in vivo
 Ileal contraction in vitro
 Gastric pH measurement
 Gastric emptying
 Intestinal motility
 Emesis induction

15. Evaluation methods
 Barium sulphate (BaSO4) or a charcoal test meal
 pylorus ligation test
Emerging techniques
 Endoscopy
 Biomarkers
 EMG Citrulline
 miR-194
 Calprotectin

16. Alternate models
 Zebrafish model: anticonvulsant activity, locomotor activity, behavioural
paradigms such as addiction, memory and anxiety.
 human embryonic stem cell derived cardiomyocytes (hESC-CM) and
human inducible pluripotent stemcell derived cardiomyocytes (hiPS-CM) as
models of in vitro high throughput drug screening and CVS safety assessment.

17. Conditions under which Studies are not Necessary
 Safety pharmacology studies may not be needed for locally applied agents.
e.g., dermal or ocular
 cytotoxic agents with novel mechanisms of action, there may be value in
conducting safety pharmacology studies.
 For biotechnology-derived products that achieve highly specific receptor targeting,
it is often sufficient to evaluate safety pharmacology endpoints as a part of
toxicology and/or pharmacodynamic studies, and therefore safety pharmacology
studies can be reduced or eliminated for these products.
 For biotechnology-derived products that represent a novel therapeutic class and/or
those products that do not achieve highly specific receptor targeting, a more
extensive evaluation by safety pharmacology studies should be considered.
 A new salt having similar pharmacokinetics and pharmacodynamics properties-
safety pharmacology studies are not necessary.

18. REFERENCES
 Safety Pharmacology Studies for Human Pharmaceuticals S7A, Current Step
4 version , dated 8 November 2000.
 Toxicology and Applied Pharmacology, Safety pharmacology — Current
and emerging concepts, YTAAP-12785; No. of pages: 10; 4C: 3
 https://www.cyprotex.com/toxicology/cardiotoxicity/hergsafety