tier 2 study in safety pharmacology.pptx

we perform safety pharmacology study to identify undesirable pharmacodynamic property of a substance that may have relevance to its human safety.

1. Safety pharmacology study Tier 2 Submitted by: Submitted to: GaJEnder dr Saumya das M.Pharma (pharmacology) (associate professor) 1 st year Niet (pharmacy institute)

2. Tier 2 safety pharmacological studies Also called as supplemental pharmacological studies. Used to access potential adverse pharmacodynamic effect on organ system function not addressed by core battery studies. It includes Renal/Urinary system Gastrointestinal system Other organ system Skeletal system Immune and endocrine functions

3. Renal studies in safety phramacology The kidney is a complex excretory organ Playing role in Fluid and electrolyte balance Control of blood pressure Removal of waste product Drug disposition Endocrine function

4. Renal studies in safety pharmacology 30-40% drugs invented can cause renal injury Still the safety pharmacological studies related to renal system in preclinical system is small.

5. Methods to access drug effects on renal function It should cover Excretory function Hemodynamic function Endocrine aspects In-vivo models are frequently used.

6. Model employed In-vivo mammalian model Glomerular function Tubular function Hemodynamic function In-Vivo Non Mammalian models In-Vitro models In-Silico model

7. In-Vivo mammalian model Rats , Dogs, Pigs are commonly used Conscious , freely moving animals Analysis of urine and plasma are done Urinary bladder catherterization and metabolism cage are used

8. 1. Glomerular function Clearance measurement of endogenous and exogenous small molecules ( ureas , creatinine , 2-MPT, insulin, cystatin c, iohexol , or indixanol ) Analysis of plasma and urine samples The noninvasive clearance(NIC)- kidney device that when mounted on the back of laboratory animals enables the transcutaneous measurement of the elimination kinetics of the fluorescent renal markers FITC- sinistrin This allows the measurement of the clearance of FITC- sinistrin from the plasma in real time without the need for any blood sampling

9. 2. Tubular function Allows the identification of the functional status of the particular nephron segments Includes visual assessment of urine (colour, clarity), volume , specific gravity or osmolarity, pH, quantitative or semiquantitative protein, and glucose content Dipstick test strips assess other parameters such as ketones, bilirubin, urobilinogen, hemoglobin etc

10. How to interpret a urine dipstick

11. 3. Hemodynamic function 1. Direct renal blood flow measurement Require the placement of a flow probe arounds the renal artery Conducted in large animal species such as dogs, pigs, and non human primate Usually coupled with systemic species such as dogs pressure monitoring using a pressure catheter placed inti an artery Another hemodynamic endpoints is the renal vascular resistance(RVR) calculated as the ratio between RBF and mean arterial pressure (MAP) RVR can be increased in case of renal dysfunction or in case of systemic hypertension

12. 2. Indirect renal blood flow measurement Para- aminohippuric acid (PAH)clearance test All PAH passing through the kidney appears in the urine PAH clearance is directly proportional to the rate of plasma flow through the kidney If the hematocrit is known, the total renal blood flow can be easily calculated from the eRPF value

13. In vivo non mammalian model The zebrafish (danio rerio) larva has gained increasing interest over the last decade as an alternative to mammalian in vivo models The zebrafish kidney is genetically and morphologically closed to the mammals Measurement of FITC insulin intensity in the caudal artery and excreted FITC insulin Validated using gentamicin and high salt loading High throughput screening visual transparency low cost and genetic manipulation

14. In vitro models In vitro model complex composed of a filter unit and a tubular segments together containing over 20 different cell type Nephrotoxicants cause injury by selectively injuring specific cell type of by non selective injuring multiple cell type with in the kidney , depending on their mechanism of action. Assessment of the potential nephrotic effect of pharmaceutical compounds of different model system In vitro model the recapitulates the in vivo response of renal cells to nephrotoxicants requires appropriate expression of the transporters and receptors that interact with the drug of interest In addition to detecting expression of transporters at the transcript and protein level by quantitative PCR and immunohistochemistry, the function of transporters and endocytic receptors can be investigated by assessing the effect of fluorescent substrates and transport inhibitors

15. In silico models The SAPHIR project ( a system approach for physiological integration of renal , cardiac, and respiratory functions initiated in 2008 Targeting the short and long term regulatory of blood pressure and body fluid ,and homoeostasis of major solutes For renal and urinary disorders, the predictivity was not very high

16. Gastrointestinal safety pharmacology 2-3 % discontinuation of drug project Related ADRs and AEs are not life threatening but hamper quality of the life for patients 18%of total ADRs Overuse of NSAIDs in US is a reason behind >100000 hospitalization and 17000 details in a year(20030 Hence there is a need for improved and more extensive GI screening

17. Evaluation methods Barium sulfate or a charcoal test meal Pylorus ligation Emerging techniques Endoscopy Biomarkers EMG citrulline MIR-194 calprotectin

18. REFERENCE www.semanticscholar.org/paper/Safety-pharmacology-%E2%80%94-Current-and-emerging-concepts-Hamdam-Sethu/bff97b062162752116bab4a3cbdbc181aad616d6/figure/3 https://www.slideshare.net/SHILPAthakur44/safety-pharmacology-ppt https://www.slideshare.net/SantoshSai10/safety-pharmacology-studies

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