K.

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

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
 Evaluation methods
 Functional observation Battery (FOB)

 Modified Irwin's test

FOB

neurotoxicological and
neuropathological investigations
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

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

 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

 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.
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.
 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)
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
 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

 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
 Evaluation methods

 Barium sulphate (BaSO4) or a charcoal test meal

 pylorus ligation test
Emerging techniques
 Endoscopy
 Biomarkers
 EMG Citrulline
 miR-194
 Calprotectin
 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.
 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.
 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