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.
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