Safety Pharmacology: Respiratory System

Safety pharmacology are Studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in therapeutic range and above

1. Seminar On, Safety Pharmacology Studies : Respiratory System Presented By POOJA HARISH SHIMPI M . Pharm Sem - I (Pharmacology) 20-07-2021 1 Smt. Kashibai Navale College of Pharmacy Kondhawa (Bk), Pune 411048

2. INDEX History Introduction : Safety Pharmacology ICH S7A Guidelines Objectives : Safety Pharmacology Safety Profile of New Drug Entity Respiratory system : A Core battery system Respiratory System safety pharmacology assessment methodology Drugs affecting functioning of respiratory system Drugs withdrawn from market due to safety issue related to respiratory system Recent updates References 20-07-2021 2

3. History The appearance of term safety pharmacology in literature dates back to 1980s. Pharmaceutical industry described term as nonclinical pharmacological evaluation of unintended effects of candidate drugs for regulatory submission. The major stimulus to discipline of safety pharmacology was released in 1996 of draft points to consider document on QT prolongation by European Medicines Agency’s (EMA) Committee for Proprietary Medicinal Products (CPMP) In 2005 , concern was addressed by issue of the ICH S7A guidelines. 20-07-2021 3

4. Introduction : Safety pharmacology Pharmacology studies are divided as : Primary pharmacodynamics Secondary pharmacodynamics Safety pharmacology studies " Safety pharmacology studies can be defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in therapeutic range and above " 20-07-2021 4

5. ICH S7A guidelines ICH : International Conference on Harmonization of Technical Requirement for Registration of Pharmaceuticals for Human Use Topic S7A : Safety Pharmacology Studies for Human Pharmaceuticals Safety pharmacology CVS ,CNS ,RS GIT, ANS, Renal CVS, CNS, RS Hierarchy of safety pharmacology study 20-07-2021 5

6. Objectives : Safety Pharmacology To identify the undesirable pharmacodynamics properties of substance that may have relevance to its human safety To evaluate adverse pharmacodynamic or pathophysiological effect of substance observed in clinical studies To investigate mechanism of adverse pharmacodynamics effects observed Early discovery Late discovery Early development Late development Marketing authorization Current/future past Onset of SP studies Onset of SP studies 20-07-2021 6

7. 20-07-2021 7 Safety Profile of New Drug Entity

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9. Respiratory system : Core battery system Drugs of various pharmacological classes are known to have deleterious effects on respiratory functions including life threatening conditions. Hence, its mandatory and detailed preclinical testing assessing the effects of new compounds on respiratory function was required. Therefore, as per the ICH recommendations, the SP assessment of the potential adverse reactions of new drugs requires evaluation of respiratory function as part of the core battery studies involving vital organ system. 20-07-2021 9

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11. 20-07-2021 11 Respiratory System safety pharmacology assessment methodology

12. Class Drugs Anticancer agents Busalfan , Chlorambusil , Cyclophosphamide. Antibiotics Nitrofurantoin , Amphotericin B , Sulfonamides . Analgesics Heroin ,Salicylates. Cardiovascular agents ACE inhibitors, Beta-blockers, Amiodarone. Antidiabetics Pioglitazone , Thiazolidinediones. SERMs Tamoxifen , Raloxifen . Drugs affecting respiratory system function Drugs known to cause pulmonary disorders 20-07-2021 12

13. Drugs that can cause other Atypical Pulmonary Patterns Pulmonary syndromes Drugs Bronchiolitis obliterans Busulfan , Gold salt , Penicillamine , Sulfasalazine Alveolar haemorrhage Clopidogrel, Cyclosporine, Epoprostenol Pulmonary infiltrates and eosinophilia Clarithromycin, Duloxetine, Diltiazem Systemic lupus erythematosus Aminoglycosides, Calcium channel blockers, Nicotine, Dantrolene. 20-07-2021 13

14. Drugs withdrawn from Market due to Safety Issues related to Respiratory System DRUGS YEAR COUNTRY REASONS FOR WITHDRAWL Proglumide 1989 Germany Respiratory reaction Fenoterol 1990 New Zealand Asthma mortality Repacuronium 2001 UK Risk of fatal bronchospasm Fenfluramine 1997 European union, US, UK, India , South Africa Pulmonary hypertension 20-07-2021 14

15. Recent updates US flags 2 top neurological drugs used in India , warns of serious breathing difficulties. USFDA warns against consumption of top selling drugs- gabapentin and pregabalin that are sold in India to treat neurological disorders – as they cause “ serious breathing difficulties” As many as the 49 reports were submitted to FDA over a 5 year period from 2012. These reports showed that 12 peoples died from “ respiratory depression ” arising from the use of gabapentenoids , according to FDA. 20-07-2021 15

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17. References Sterner W, Korn WD (1980). " Zur Pharmakologie und Toxikologie von Etofyllinclofibrate ". Arzneimittel Forschung . 30 (11b): 2023–31. PMID 7194053. Redfern WS, Wakefield, ID (2006) Safety Pharmacology. In Toxicological Testing Handbook: Principles, Applications and Data Interpretation, 2nd edn ., 33-78. S7A Safety Pharmacology Studies for Human Pharmaceuticals, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER),July 2001,pp.2-3 J. Hamdam et al. / Toxicology and Applied Pharmacology 273 (2013), Elsevier, 229–241 Murphy, D.J., Assessment of respiratory function in safety pharmacology. Fundam . Clin. Pharmacol . 16, 2002,183–196. 20-07-2021 17

18. 20-07-2021 18 MK Pugsley, S Authier and MJ Curtis, Principles of safety pharmacology , British Journal of Pharmacology (2008) 154, 1382–1399. Nancy L. Fagan , Pamela A. Foral , Mark A. Malesker , Lee E. Morrow, Therapeutic Update on Drug-Induced Pulmonary Disorders, US Pharm. 2011;36(7):HS3-HS8. David Montani , Andrei Seferian , Laurent Savale , Ge´rald Simonneau and Marc Humbert, Drug-induced pulmonary arterial hypertension: a recent outbreak, ERSpublications , Eur Respir Rev 2013; 22: 244–250 Fung, M.; Thornton, A.; Mybeck , K.; Wu, J. H.-h.; Hornbuckle, K.; Muniz, E. "Evaluation of the Characteristics of Safety Withdrawal of Prescription Drugs from Worldwide Pharmaceutical Markets-1960 to 1999".  Therapeutic Innovation & Regulatory Science . 1 jamuary 2001, 35  (1): 293–317. Qureshi, ZP; Seoane -Vazquez, E; Rodriguez- Monguio , R; Stevenson, KB; Szeinbach , "Market withdrawal of new molecular entities approved in the United States from 1980 to 2009".  Pharmacoepidemiology and Drug Safety .,SL (July 2011).   20  (7): 772–7 .

19. 20-07-2021 19 THANK YOU