Drug Safety MBBS Accessible Slides - Tagged PDF

DD/Month/YYYY Professor/Dr: Topic title: Dr Manasi Nandi Department of Pharmacology: Medicine’s development [email protected] Pharmacology Toxicology and Drug Safety DD/Month/YYYY Professor/Dr: Topic title: Learning Outc...

DD/Month/YYYY Professor/Dr: Topic title: Dr Manasi Nandi Department of Pharmacology: Medicine’s development [email protected] Pharmacology Toxicology and Drug Safety DD/Month/YYYY Professor/Dr: Topic title: Learning Outcomes After this lecture, you should be able to: Describe the stages of the medicines discovery and development pathway Explain the concept of Benefit:Risk ratio when developing/prescribing medicines Define and understand the terms ‘adverse drug reaction’ ‘on target effects’ ‘off target effect’ and ‘safety window’ Understand how adverse drug reactions may arise in humans and what can influence this Describe the types of study that identify safety risk of compounds in development Understand the key players involved at different stages of medicine development DD/Month/YYYY Professor/Dr: and licensing Topic title: A note on language “Drug” and “medicine” are used interchangeably - in both cases I mean ethical medicines i.e. those that are approved by medicines regulators “Side effects” = “adverse drug reactions” Risk= safety concerns (identified from experimental data) ‘Lead candidate’ = ‘lead compound’ – molecule being developed to eventually become a ‘medicine’ Discovery – earliest stages of research validating the target and identifying lead compound Development- later stage series of experiments which are regulated and necessary to progress compound into human testing 4 As a medical student, why do I need to know this? As a qualified doctor you are likely to: prescribe medicines for your patients provide ongoing care for patients taking multiple medications encounter patients who are unresponsive to medication encounter patients who experience adverse drug reactions(which may reduce compliance) make decisions about starting or withdrawing treatment based on patient/disease characteristics make wider risk:benefit decisions on behalf of each patient (quality of life/life expectancy) make judgements about new treatments that come onto the market which require you to interpret data from medicine development research studies If you understand how medicines are developed and tested for safety and efficacy – you will make more informed decisions when using them 5 Aren’t all medicines safe? Would you take this drug for a sports muscle injury? Potential adverse effects: Stomach pain, indigestion, feeling sick, vomiting, diarrhoea, constipation, flatulence Bleeding from stomach or bowels or worsening of existing conditions such as colitis or Crohn’s disease Stomach Ulcers Liver or kidney problems Severe sore throat, high fever and flu like symptoms Severe headache, stiff neck, nausea, confusion Stevens-Johnson syndrome (skin peeling off) Wheezing, SOB, skin rash Blood disorders, swelling, high BP, , heaty failure, blurred vision Chicken pox (varicella) infection And more…. To answer this question, it would be important to understand the relative risk to you and the anticipated benefit of the medicine 6 Benefit: risk ratio A cornerstone of medicines development and patient prescribing Benefit the medicine will bring to the patient Vs. Risk of adverse drug reaction This Photo by Unknown Author is licensed under CC BY-SA Would you take/prescribe an allergy medication if you knew the side effect was complete hair loss, nausea, vomiting? Would you take/prescribe an anti-cancer therapy with the same anticipated adverse effects? 8 What just informed your decision? Patient considerations: Medicine considerations: Allergies: Antihistamine: Population: paediatric - elderly Prescribing: over the counter widely available Symptoms: itchy, runny eyes, sneezing, disturbed sleep Impact: disruptive but not usually life Intended therapeutic effects: to alleviate symptoms changing/threatening, seasonal presentation (histamine receptor antagonist) Acceptable adverse effects: Drowsiness? Lung cancer Population: >40 yrs, typically >75 Chemotherapy: Symptoms: cough, blood/phlegm, wheezing, fatigue – weakness, CV effects, seizures, coma Prescribing: oncologist Impact: life threatening; 23% survival rate >5 years; Intended therapeutic effects: attenuation of tumour recurrant growth; increased life expectancy Acceptable adverse effects: Drowsiness? Nausea? Vomiting? Hair loss? TREATMENT BENEFIT HIGH IN LUNG CANCER PATIENTS HIGHER ACCEPTABLE RISKS WITH CHEMOTHERAPY 9  Pharmacology and toxicology - in quotations “dosis sola facit venenum” = “only the dose makes the poison” Philippus Aureolus Theophrastus (aka Paracelsus) 1493-1541 “Every drug has two actions – the one you know about, and the one you don’t” Sir John Gaddum 1900-1965  As a future prescriber you need to remember: The dose distinguishes a poison from a remedy Some adverse drug reactions are predictable, other are unknown 100 Therapeutic Unacceptable Range Toxicity/Pharmacology 80 Confidence in: 60 Effect Efficacy v Safety 40 20 0 10 100 1000 10000 Dose or Exposure What is an acceptable margin for each new drug will depend on  Risk:benefit (Safety vs Efficacy) 11  The Therapeutic Area (e.g. oncology vs hayfever) How do drugs elicit adverse drug reactions/effects? Direct or metaboliteAbnormal apoptosis Tumours, damage to or necrosis of cellsChanges in organ function DNA Organ damage (Toxicological Immune response microscopic) (Pharmacological/macroscopic) Direct effect on an intended or unintended molecular target / biochem pathway Intended vs.unintended target When considering medicines: Intended target – ON TARGET EFFECTS: The protein (e.g. receptor, ion channel) we want the medicine to interact with, to elicit a therapeutic response. e.g. propranolol - binding to b1 andrenoceptors in the heart to reduce heart rate for anxiety Unintended target –OFF TARGET EFFECTS Many drugs are promiscuous and will bind to other proteins in the body. The trick is to make sure they stick less tightly to unintended proteins (less affinity). e.g. propranolol – binding to b2 adrenoceptors in the lungs, narrow airways and cause difficulty breathing ALL ABOUT THE RIGHT DOSE IN THE RIGHT TISSUE! 13  How can a drug go from being therapeutic to eliciting an ADR? Drug overdose—Toxic reactions linked to excess dose or impaired excretion, or to both (intended – suicidal or unintended-renal dysfunction) Drug adverse/side effect—Undesirable pharmacological effect at recommended doses (often hyperpharmacology) Drug interaction—Action of a drug on the effectiveness or toxicity of another drug (also could be e.g. drug-diet interaction) Clinical Review ABC of allergies Adverse reactions to drugs BMJ 1998; 316 doi: http://dx.doi.org/10.1136/bmj.316.7143.1511 The expression of adverse drug reactions can be influenced by numerous factors. Such susceptibility factors include: Age Underlying disease Pregnancy Genetics (polymorphisms) in target/off target proteins Diet (e.g. altered metabolism) Occupation (i.e. exposure to other agents) Drug-drug interactions (if person on another medication can alter ADME of another compound)  The medicines discovery and development pathway – helps us understand, predict and manage risk of new medicines DISCOVERY DEVELOPMENT Post Lead Candidate Pre-Clinical Clinical Hits marketing identification Optimisation Development Development surveillance Identify a lead candidate drug Test lead candidate drug from thousands of compounds extensively Does it hit the right target for efficacy and safety (efficacy)? Regulated procedure in animals What are the initial warning and humans signs for adverse effects ~3 years (safety)? > ~8 years 16 Pause and recap…. After this lecture, you should be able to: Describe the stages of the medicines discovery and development pathway Explain the concept of Benefit:Risk ratio when developing medicines Define and understand the terms ‘adverse drug reaction’ ‘on target effects’ ‘off target effect’ and ‘safety window’ Understand how adverse drug reactions may arise in humans and what can influence this Describe the types of study that identify safety risk of compounds in development Understand the key players involved at different stages of medicine development and licensing 17 The medicines discovery and development pathway: SAFETY DISCOVERY DEVELOPMENT Post Lead Candidate Pre-Clinical Clinical Hits marketing identification Optimisation Development Development surveillance Identify a lead candidate drug Test lead candidate drug from thousands of compounds extensively Does it hit the right target for efficacy and safety (efficacy)? Regulated procedure in animals What are the initial warning and humans signs for adverse effects ~3 years (safety)? > ~8 years 18 International guidelines to support consistency of Quality, Safety and Efficacy 19 Safety assessment in the drug discovery and development pipeline DISCOVEY Candida DEVELOPMENT Pre- Post Lead Clinical te Clinical marketing Hits identifica Developm Optimis Developm surveillanc tion ent ation ent e Identifying risk – pulling out high risk compounds Pre: First in Human Confirming safety/toxicity profile Monitored by independent regulatorsTesting in humans with some ongoing animal studies in background Monitored by independent regulators  Safety assessment in the drug discovery pipeline Integrate in silico, in vitro, chemical property and pharmacokinetic data Candida Lead te Primary Pharmacology on-target Hits identifica Optimis profiling. tion ation Tissue expression, anticipated adverse effects Identifying risk – pulling out high Secondary Pharmacology off- risk compounds target Profiling- Receptors, channels, enzymes Something in the structure? WIDE LIGAND Examples of in PROFILING vitro safety Interaction with other proteins and could this be a problem? screens Cell/protein specific interactions e.g. Cardiovascular: Ion chennel ion channels screening, In vitro testing – iPS Cardiomyocyte function genotoxicity/mutation risk? CNS: Ion channels, electrophysiology Liver: Hepatopcytes, Mitochondrial toxicity, GSH General Toxicology: different cell lines e.g.monocytes  Safety assessment in the drug pre-clinical development pipeline DISCOVEY DEVELOPMENT Post Candida Pre- Lead Clinical te Clinical marketing Hits identifica Developm Optimis Developm surveillanc tion ent ation ent e Identifying risk – pulling out high risk compounds Confirming safety/toxicity profile – regulated GLP Toxicology – using higher and higher doses over chronic periods (weeks, months) – to identify tissues/organs at highest risk Safety pharmacology – using therapeutic dose range to identify any acute effects on ‘core battery’- CV, CNS, In vivo toxicology – using research animals to understand types of ADR at very high doses over long time periods Giving increasing doses of drug above the therapeutic range (efficacy range)over days/weeks/month In life observations Post mortem histology Aim is to expose animals to very high concentrations of the compound to see at what point it becomes toxic Can help identify which organs/tissues/systems are at greatest risk – to assist with clinical trials Can assist with defining safe concentration ranges In vivo safety pharmacology – using research animals to understand short term effects at therapeutic doses on vital organs Determine if compound has adverse effects on ‘Core battery’ at therapeutic dose for ~24 hours Cardiovascular, Central Nervous System and Respiratory Also can look at GI, Renal in special circumstances if required Use techniques such as radiotelemetry (blood pressure, ECG, heart rate), plethysmography (lung function) or observe changes in CNS function (drowsiness, seizures, anxiety, motor function) in living conscious animals. Check point: the role of regulators To appraise all preclinical data ensuring efficacy, safety and quality endpoints are met before medicine can be tested in human subjects 25 Safety assessment in clinical development: assessing ADR in human volunteers and patients Clinical trials Ph Ph Ph Ph 1 Careful selection of 2 3 4 Optimal dose range Post market safe starting dose Exclusion criteria as approprate surveillance – GP Based on animal Careful recorded observation and electronic studies Balance anticipated acceptable ADR reporting ‘yellow Observation of with serious ADR card’ system an adverse effects in Frequency of ADR example – a drug participants Only in certain patient groups? must be monitored Placebo controlled Suspend or terminate if efficacy end for the whole time Suspend or points unmet or safety risk too high it is in use. terminate if high frequency serious ADR Bringing it all together – key players Licensed for use EFFICACY SAFETY Prescribers, pharmacists, Biomedical and medicine Regulators and clinicians Always monitoring development scientists (pharmacovigilance) Safety, efficacy and quality Safety, efficacy, quality The importance of patient information leaflets…. These provide instructions on recommended dosing Ibuprofe n (see pharmacokinetics lecture) The importance of patient information leaflets…. …and ‘possible side effects’ Ibuprofe n Pause and recap…. After this lecture, you should be able to: Describe the stages of the medicines discovery and development pathway Explain the concept of Benefit:Risk ratio when developing medicines Define and understand the terms ‘adverse drug reaction’ ‘on target effects’ ‘off target effect’ and ‘safety window’ Understand how adverse drug reactions may arise in humans and what can influence this Describe the types of study that identify safety risk of compounds in development Understand the key players involved at different stages of medicine development and licensing 30 Summary The medicines discovery and development pipeline generates data to demonstrate a drug works (efficacy) and to understand potential ADRs (safety) All medicines can be toxic and lead to ADRs – it all depends on the dose. This safe and effective dose range is experimentally determined At each stage of the pipeline, scientists and regulators weigh up data at each stage to ensure the benefits of the medicine outweigh the risks Some risks can be predicted by the ‘on target or intended’ effects of the drug. Off target effects are identified during the pipeline but there can still be ‘unknown’ potential ADRs Not all medicines will always cause ADR in all patients – many factors influence this In vitro and in vivo experiments in animals help to identify risk of ADRs to humans Clinical development studies (trials) – prove whether drug is efficacious and safe in humans Scientists, doctors and regulators all work together – sharing information to ensure safe, effective medicines are made available to the public and monitored whilst in use 31 For any questions please contact me at: [email protected]