Safety pharmacology studies in drug development

In the given ppt we get idea about safety pharmacology studies. learn why safety pharmacology is important. concept of safety pharmacology, also get the knowledge from where safety pharmacology is originated

1. Safety pharmacology studies SUBJECT NAME : PHARMACOLOGICAL AND TOXICOLOGICAL SCRRENING METHOD-II GUIDED BY: DR. A. K. KULKARNI PRESENTED BY: ANKITA SANDESH HALDANKAR (M. PHARM 1 ST YEAR PHARMACOLOGY) D. Y. PATIL COLLEGE OF PHARMACY AKURDI , PUNE

2. CONTENT INTRODUCTION ORIGIN CONCEPT IMPORTANCE OF SAFETY PHARMACOLOGY

3. INTRODUCTION As per ICH S7A safety pharmacology are those studies that investigate the potential undesirable pharmacodynamic effect of substance on physiological function in relationship to exposure in therapeutic range & above . Sometimes primary & secondary pharmacodynamic properties of substance may contribute to this safety evaluation for potential adverse effect in humans. Safety pharmacology evaluation are essential step in assigning acute & potential life threatening risk of novel pharmaceutical as a part of IND enabling program. Safety pharmacology study use to determine mechanistic effect vital functions & evaluate potential adverse effect as organ effect such as renal, GI tract.

4. Origin of safety pharmacology Serious injury or death of voluntary & patient participate in early clinical trial are ray & thus distribute when it occurs the organ system and function most frequently responsible in this events of cardiac vascular, respiratory, CNS and Renal system and their result almost always critical emergency. The origin of safety pharmacology are grounded upon observation that organ functions can be toxicological target to humans expose to normal therapeutic agents and that drugs effect on organs functions are not readily detected by standard toxicological testing .

5. Concept of safety pharmacology OBJECTIVE OF STUDIES To identify undesirable pharmacodynamic properties of a substance that may hamper the human safety. To evaluate adverse pharmacodynamic & pathological effect of substance observe in toxicology or clinical studies. To investigate mechanism of adverse pharmacodynamic effect observed or suspected. OBJECTIVE OF STUDIES To identify undesirable pharmacodynamic properties of a substance that may hamper the human safety. To evaluate adverse pharmacodynamic & pathological effect of substance observe in toxicology or clinical studies. To investigate mechanism of adverse pharmacodynamic effect observed or suspected.

6. 2 . GENERAL CONSIDERATION IN SELECTION & DESIGN OF SAFETY PHARMACOLOGY STUDIES The pharmacological affects varies as per specific properties of test substance so study should selected & design accordingly. Design of study should be as per class of drug may it should suggest specific adverse effect of that class. Ligand binding enzymes assay that suggesting a potential for adverse effects. Adverse effects associate with member of chemical or therapeutic class but independent of primary pharmacodynamic effect. Result from this Previous safety pharmacologic studies Secondary pharmacodynamic studies Toxicology studies Previous human use

7. 3. Test system General consideration on test substance Use of in vivo & in vitro studies Experimental design Sample size & use of control Route of administration A.General consideration on test substance The consideration should be relevant to selection of animal model or other test system or that scientific valid information can derived. Selection factor can include pharmacokinetic profile. Pharmacodynamic responsible of model, species, strain, gender, age of experimental animal. susceptibility, sensitivity & reproducibility of test system.

8. B . Use of in vivo & in vitro studies In vivo & in vitro System can be include isolated organs & tissue, cell culture, cell fragments, Subcellular organelles, receptor & channel, transporters & enzymes. In vitro system can be we in supportive studies. for example to obtain profile of activity of substance to investigate mechanism of effect. For conducting in vivo studies is prefer to use anesthetize animal.

9. c ) Experimental design Sample size & Use of control Size of group should be sufficient to allow meaningful scientific interpretation of that generated i.e. each group a sufficient animal should be included to conclude the final that & no.at animal should be such so the presence of biologically significant effect of that Substance should be evaluated. (ii ) Route of administration the expected clinical route of administration should be used when possible. Study previous that in human if such information is available assessment effects by more than one route may be appropriate. If the test substance is intended for clinical use by more than one route of administration i.e. either oral / Parenteral

10. 4.Dose level or conc. of test substance It divided into In vivo & In vitro studies. In vivo Studies. Define the dose response curve of adverse effect The time course of adverse effect shows be investigate when possible. b) In vitro studies In vitro studies should be designed to establish a conc. effect relationship. The range of conc. should be use in order to increase the likelihood of detecting and effect of test substance. 5. Duration Safety pharmacology studies are generally performed by single dose administration. Safety studies should be Rationale based it following condition occurs For example pharmacodynamic effect occur only after certain duration of treatment If result from repeated dose non clinical studies. If adverse effect result from use in humans.

11. 6. Safety pharmacology core Battery It is performed according to GLP std. as per ICH guideline Purpose To investigate the effects of test substance on vital functions & vital organs which include. CNS Cardiovascular System Respiratory system It is also implements Supplementary test to evaluate other organ system like renal & &GI system

12. 7 . Follow-up & supplemental safety pharmacology studies concern of adverse effect may arise from Safety Pharmacology core battery clinical trial Pharmacovigilance. Experimental in vitro or in vivo studies

13. 8 . 1) Follow up studies f or s afet y Pharma co logy core battery Deal with studies follow up studies provide greater depth of understanding & additional knowledge to that provide by core battery on vital functions. T he following list of studies fur ther evalu a te vital organ system for potential adverse pharmacodynamic effects. C NS Behavioral Pharmatology, leaming & memory , ligand Spe cific binding , neurochemistry, visual , auditory, electrophysiology examination etc C a rdiovascular System cardiac output , ve ntr icular con tractility , vascular resistance, the effect of endogenous or exogenous substance o n Cardiovascular response etc Respiratory s yste m Air way resistance, compliance, pulmonary arterial pressure, bl ood g a ses, blood pH etc

14. 8.11) Supplemental safety pharmacology studies They are meant to evaluate adverse pharmacodynamic effects on organ system that not addressed by core battery studies. Renal/Urinary system Effects of test substance on renal parameter should be assessed for e.g. urinary volume, Specific gravity. osmolarity, pH, electrolyte balance, proteins & blood chemistry determination such as blood, urea, nitrogen, Creatinine & plasma Protein to be used Gastrointestinal System Effect of test substance on GI system should be assessed for e.g. gastric secretion, GI injury potential, bile secretion, transit time in vivo, illegal contraction in vitro gastric PH measurement and pooling can be used.

15. A NS Effect of test substance on ANS should be assessed for example binding to relevant receptor, responses to agonist or antagonist, measurement of cardiovascular responses and heart rate variability can be used. Other organs system Effect of test substance on organ system not investigated elsewhere should be assessed when there is a recon for concern Example: skeletal muscle, immune and endocrine functions can be investigated.

16. 9.Condition under which studies are not necessary Safety pharmacology studies may not be needed For locally applied agents. ( example dermal or ocular) For cytotoxic agent for treatment of end- stage cancer patient. For biotechnology derived products that achieve highly specific receptor targeting. For exceptional cases like that of a new test substance having similar pharmacokinetic and pharmacodynamic profile .

17. 10.Timing of safety pharmacology studies in relation to clinical development When planning a safety pharmacology program should be reviewed to determine whether or not specific studies are recommended. Studies prior to administration in humans Studies during clinical development Studies before approval

18. Importance of safety pharmacology Safety pharmacology issues have a significant impact on clinical development attrition ( both preclinical and during clinical development). Data are important for phase-1 dose setting Safety pharmacology studies are regulatory requirement for IND submission prior to human exposure. The consequence of getting it wrong can have dramatic implication. Minimize unreliability of patient on pharmaceuticals via enduring safety. Ensure safety before clinical phase so validate preclinical phase to better extent .

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