Safety pharmacology

Safety pharmacology studies for respiratory, CNS and CVS system

1. SAFETY PHARMACOLOGY Presented by Grandhi Sandeep Ganesh Dept. of Pharmacology 1

2. PHARMACOLOGICAL PROFILING 2

3. ADVERSE DRUG REACTIONS TYPE TERM CHARACTERISTICS A Augmented Dose dependent, frequent, explained by pharmacological drug effect B Bizarre Dose independent, rare, unpredictable C Chronic Dose and Time dependent D Delayed Time dependent, rare E End of treatment Time dependent, rare https://www.futurelearn.com/courses/allergies/0/steps/68785 3

4. GUIDELINES 4 https://www.ich.org/page/safety-guidelines

5. PHARMACOLOGY STUDIES 5 https://www.ich.org/page/safety-guidelines

6. SAFETY PHARMACOLOGY Safety pharmacology studies are defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above 6 https://www.ich.org/page/safety-guidelines

7. 7 Safety pharmacology Core battery supplemental Follow-up SAFETY PHARMACOLOGY CNS CVS RESPIRATORY GIT RENAL EMEA 2006

8. OBJECTIVES OF SAFETY PHARMACOLOGY STUDIES To identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety To evaluate adverse pharmacodynamic or pathophysiological effects of a substance observed in toxicology studies To investigate the mechanism of the adverse pharmacodynamic effects observed 8 https://www.ema.europa.eu/en/documents/scientific-guideline/ich-s-7-safety-pharmacology-studies-human-pharmaceuticals-step-5_en.pdf HAZARD IDENTIFICATION RISK ASSESSMENT RISK MANAGEMENT/MITIGATION

9. IMPORTANCE Safety pharmacology issues have a significant impact on clinical development attrition (both preclinical and during clinical development) Data are important for Phase I dose-setting Safety pharmacology studies are a regulatory requirement for IND submissions prior to human exposure The consequences of ‘getting it wrong’ can have dramatic implications 9 Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

10. APPLICATIONS Prevention of serious ADR in FIH studies Understanding the concentration-response relationship for any effects on major physiological systems that may be predictive of AE in man In combination with other safety data, safety pharmacology should be used to select the starting dose for FIH Support mechanistic understanding of AE in clinical trials 10 Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

11. RESPIRATORY SAFETY PHARMACOLOGY Respiratory Safety Pharmacology as described in ICH S7A core battery aims to evaluate the effects of a test substance on pulmonary function The basic procedure uses whole body plethysmography.Several supplementary and follow-up studies can be designed to further evaluate the effects on respiratory function 11 Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

12. RESPIRATORY SAFETY PHARMACOLOGY CORE BATTERY STUDIES Respiratory rate tidal volume hemoglobin oxygen saturation 12 FOLLOW UP STUDIES airway resistance compliance pulmonary arterial pressure blood gases blood pH. Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

13. 13 RESPIRATORY SAFETY PHARMACOLOGY Evaluation of respiratory functions Pumping efficiency Gaseous exchange Function Regulates gas exchange between environment and airways Function Regulates gas exchange between airways and blood Components Respiratory muscles Components Airways,alveoli,fibrous network Core measurements Tidal volume,respiratory rate,minute volume Core measurements Dynamic airway resistance & lung compliance Junnat H, Swaminathan S Safety pharmacology — Current and emerging concepts

14. RESPIRATORY RATE AND TIDAL VOLUME Plethysmograph chambers Head-out or head-enclosed volume displacement chambers Face mask with Pneumotachometer AIRWAY RESISTANCE & LUNG COMPLIANCE Head out or head enclosed plethysmograph chambers Facemask with Pneumotachometer Pressure sensitive catheter 14 RESPIRATORY SAFETY PHARMACOLOGY Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

15. HEAD-OUT PLETHYSMOGRAPH CHAMBER 15 Rat head-out chamber Dog head-out chamber Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

16. PNEUMOTACHOGRAPH 16 Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

17. FUNCTIONAL ENDPOINTS 17 Inspiratory Time ( Ti , ms ) Expiratory Time ( Te , ms ) Peak Inspiratory Flow (PIF, ml/s) Peak Expiratory Flow (PEF, ml/s) Tidal Volume V t (TV, ml) Respiratory Rate ( ResR , breaths/min) Relaxation Time (Tr, ms ) Pause = ( Te - Tr)/Tr Minute volume (MV, ml/min) = (TV x ResR ) https://www.porsolt.com/contract-research_safety-pharmacology_core-battery-regulatory-package_respiratory-studies.phtml

18. PLEURAL AND ARTERIAL PRESSURE MEASUREMENTS 18 Dennis J. Murphy Respiratory Function Assays in Safety Pharmacology

19. CNS SAFETY PHARMACOLOGY 19

20. CNS SAFETY PHARMACOLOGY 20 Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

21. APPROACHES TO STUDY ADR’S INVITRO STUDIES Neuronal cultures Invitro electrophysioslogy (Ion channels,neurons,slices ) INVIVO STUDIES Behavioral Neurophysiology recordings(EEG,ERG,EMG,NERVE CONDUCTION VELOCITY) Neuro chemical ( invivo microdialysis,biomarkers ) Neuroimaging (MRI) Post mortem ( neurohistopathology ) 21 Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

22. INVITRO VS INVIVO Mainly use invivo methods in conscious animals ,reason is cns function is best evaluated in intact and freely moving animals ETHICAL AND ANIMAL WELFARE ISSUES As procedures involving living animals, important considerations in the choice of method ,to avoid stressful procedure as much as possible In field of safety pharmacology, aim is to assess the risk of inducing unwanted effects, the possibility of causing animal distress is high than in other areas of pharmacology The experimenter must therefore maintain awareness of issues, not only planning and revising the protocols but also during the experiment 22 Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

23. CNS CORE BATTERY STUDIES General behavioural signs (Irwin test) Spontaneous locomotion (activity meter test) Neuromuscular coordination (Rotarod test) Convulsive threshold (Electro convulsive shock) Interaction with hypnotics (Barbital interaction test) Effects on pain threshold (Hot plate test) Others-tail flick method, morris water maze, passive avoidance 23 Junnat Hamdama Safety pharmacology Current and emerging concepts

24. IRWIN TEST This method is to evaluate the qualitative effect of test substance on behavioural and physiological functions and also duration of action The parameters observed are AUTONOMIC EFFECTS SENSORIMOTOR EFFECTS NEUROMUSC ULAR EFFECTS BEHAVIOURAL EFFECTS Salivation Touch response Posture Arousal Lacrimisation Palpebral reflex Grip strength Vocalisation Pilorection Startle reflex Tremor Aggressiveness Rectal temperature Pinna reflex Traction response Sniffing Abnormal urination, defecation, respiration Writhing reflex Twitches Grooming 24 Will Redfern Safety Pharmacology of the Nervous System

25. IRWIN TEST Conclusion This test provide a rapid detection of test substances toxicity, active dosage range Effects on behavioural and physiological function Modification: Functional Observation Battery(FOB) 25 Will Redfern Safety Pharmacology of the Nervous System

26. ACTIVITY METER TEST It is a automated apparatus with large no.of animals,less labour ,more precise statistical analysis The quantitative data obtained enable the generation of dose response curve and more precise estimation of MED and ED50 EVALUATION Rearing movements and locomotion Comparision of single photo beam interruptions with paired interruptions The data is usually analysed by students T test 26 Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

27. Critical assesment This test estimate whether the test substance possess psychostimulant or sedative activity Modifications to method Interrupting of photo electric beams Activity wheels Changes in electromagnetic fields Doppler effects Video image analysis Telemetry Detections of vibrations generated by animals 27 ACTIVITY METER TEST Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

28. SUPPLEMENTAL STUDIES Automated video systems Integrated video systems EEG Telemetry In vitro hippocampal brain slice assay 28 Junnat Hamdama Safety pharmacology Current and emerging concepts Vincent C, Christelle F Colle aux Central Nervous System (CNS) Safety Pharmacology Studies

29. OFF TARGETS TARGET MAJOR ORGAN SYSTEM EFFECTS Acetycholinesterase CNS Muscle paralysis Dopamine receptors CNS Depression ,dystonia GABA a receptor CNS Ataxia,muscle relaxation M1 CNS Vagal effects Nicotine receptor CNS Nausea,sweating,tremors Noradrenaline receptor CNS Locomotor activity Mu receptor CNS Hypothermia,sedation Kappa receptor CNS Dysphoria,confusion Delta receptors CNS Psychometric effects 5HT 1A CNS Reduced REM sleep 5HT 1B CNS Cerebral constriction 5HT 2A CNS Hallucinations 29

30. STATISTICAL ANALYSIS TYPE I ERRORS: false positive errors TYPE 2 ERRORS: false negative errors type 2 errors should be decreased as much possible, even if there is increase risk of type 1 errors 30

31. CVS SAFETY PHARMACOLOGY 31

32. SAFETY PHARMACOLOGY In the last few decades, a large number of drugs have been withdrawn from the market due to adverse cardiovascular system (CVS) effects, which were responsible for 45% of post-approval withdrawals It is important to note that QT prolongation has resulted in one third of all drug withdrawals between 1990 and 2006 due to the risk of developing fatal arrhythmias. 32

33. GUIDELINES QT interval prolongation by terfenadine has led to implementation of ICH S7B 33

34. CARDIOVASCULAR SYSTEM ASSESSMENT 34

35. PARAMETERS Arterial Blood Pressure (ABP, mmHg) Left Ventricular Pressure (mmHg) Heart Rate (HR, bpm) PR interval ( ms ) QRS interval ( ms ) QT and corrected QT https://www.porsolt.com/contract-research_safety-pharmacology_core-battery-regulatory-package_in-vivo-cardiovascular-studies.phtml 35

36. hERG  (  h uman  E ther-à-go-go - R elated  G ene) is a gene ( KCNH2 ) that codes for a protein known as  K v 11.1 the alpha subunit of a potassium ion channel the hERG channel mediates the repolarizing  I Kr  (inward rectifier potassium current) current in the cardiac action potential, which helps coordinate the heart's beating HERG ASSAY 36

37. HERG ASSAY There is considerable focus on the promiscuous hERG channel, which mediates an inward current, that, when blocked, slows myocardial repolarisation associated with prolongation of the QT interval in the ECG. This prolongation lengthens the duration of the cardiac action which appears to be a critical contributing factor in the development of a fatal arrthymia : Torsades de Pointes The effects of an NCE on the hERG channel can be detected using screening methodologies such as radio-labelled ligand binding and automated voltage clamp assays. 37

38. TELEMETRY The telemetry device consists of the implantable transmitter, which measures the pressure. This device contains a highly stable, ion implant, semiconductor, strain-gauge sensor and Arterial pressure is transmitted to the sensor via a 0.7-mm diameter, fluid filled catheter; the receiver which detects the signal from the implanted transmitter and converts it to a form readable by computer; the pressure reference module, which measures atmospheric pressure to allow for the telemetered absolute pressure to be converted to a gauge pressure; the data acquisition software, which accepts data from the reference module and the receivers 38

39. OFF TARGETS Target Major organ system Effect(s) Acetylcholinesterase Cardio vascular CV collapse Adenosine A1 receptor Cardio vascular Bradycardia, AV block Calcium channel Cardio vascular Hypotension Dopamine D1 receptor Cardio vascular Hypotension Histamine H1 receptor Cardio vascular Histamine H1 receptor Muscarinic M1 receptor Cardio vascular Vagal effects, blood pressure changes, Phosphodiesterase 3A Cardio vascular Increase heart rate Potassium channel hERG Cardio vascular QT prolongation Potassium channel KCNQ1 Cardio vascular Hypotension Sodium channel Cardio vascular Prolonged QRS interval, B.H. Morimoto et al. Safety Pharmacology in Drug Discovery and Development 39

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