Tier 1 and Tier 2 studies

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