L9 Safety Pharmacology And Toxicology PDF

L9 Safety Pharmacology and Toxicology Safety Pharmacology Part 1 [email protected] Many papers cited in these lectures are from J Pharmacol Toxicol Methods, which publishes...

L9 Safety Pharmacology and Toxicology Safety Pharmacology Part 1 [email protected] Many papers cited in these lectures are from J Pharmacol Toxicol Methods, which publishes an annual themed issue on safety pharmacology See also Pugsley MK, Authier S, Curtis MJ. Principles of Safety Pharmacology. Br J Pharmacol 154: 1382-1399, 2008  Safety pharmacology: what is it? Detection of potential adverse drug reactions (ADR) at the therapeutic dose and above Primary Pharmacodynamic Studies Detection of potential ADRs mediated by the intended molecular target (e.g., receptor) Secondary Pharmacodynamic Studies Detection of potential ADRs mediated by ‘off target’ actions Thus safety pharmacology is detection of ADR liability (liability is a fancy term for ‘risk of’) Above: blood dose might be higher than intended. Safety pharmacology begins with tests on cells and animals and continues once the drug is on the market. Primary pharmacodynamic adverse effect = takes a beta blocker for high blood pressure, causes decreased heart rate. On target = effects from intended molecular target Secondary pharmacodynamic adverse effect (off target) – effects because of a lack of specificity – drug acts on different target. Liability = risk 2  Dosage “Poison is in everything, and nothing is without poison. The dosage makes it either a poison or a remedy” Paracelsus 1493 – 1541 Dosage is what makes something a medicine or a poison. Too high a dose will always cause adverse effects. 3  Dosage, benefit and risk A substance is a drug if benefit exceeds risk At overdosage risk exceeds benefit by definition Therapeutic window All therapeutic drugs can evoke ADRs There is a therapeutic window if there is a dose or concentration range where: Taking the drug is judged to be better for the patient than not taking the drug In other words the effect of the disease would be worse than the ADRs of the drug The therapeutic window is therefore the target range of dose or concentration when a drug is used therapeutically 4  Therapeutic window = the range of dose at which a drug is producing benefit without producing significant adverse effects. You need to use animal models of disease to determine therapeutic window. Therapeutic window The likely dosage for benefit is determined from animal models of disease The likely dosage for causing ADRs is determined from safety pharmacology (SP) studies, and together this reveals: No Observable Effect Level (NOEL) – highest dose at which no therapeutic effect is detected (= threshold dose for benefit) No Observable Adverse Effect Level (NOAEL) – highest dose at which no ADR is detected (= threshold dose for ADRs) The difference is a guide to the possible therapeutic window Difference between NOEL and NOAEL = therapeutic window. 5  Therapeutic window The therapeutic window is therefore determined from: The NOEL and NOAEL with allowances for The severity of the disease and The severity of the ADRs If the target disease is lethal, the drug may have value even if it causes serious ADRs at the same dose needed for benefit For cancer, for example, the necessary therapeutic window may be much narrower than the difference between the NOEL and NOAEL Drug discovery for such a disease will be focused now on finding alternative drugs with less severe ADRs and higher NOAELs Context is very important in determining the therapeutic window. Severe diseases will have more serious adverse effects tolerated. 6  Therapeutic window The therapeutic window is therefore determined from: The NOEL and NOAEL with allowances for The severity of the disease and The severity of the ADRs If the target disease is innocuous, the drug may be deemed unusable even if it causes only minor ADRs at a dose a little above that needed for benefit For hayfever, for example, the necessary therapeutic window will be close to the difference between the NOEL and NOAEL Drug discovery will focus now on finding alternative drugs with higher NOAELs and lower NOELs The maximum ‘safe’ concentration (MSC) is thus a relative concept and is set by risk:benefit analysis: Detriment from ADRs vs benefit obtained by taking the drug 7  Pharmacokinetics also determine if something is a drug – how quickly is the drug metabolized? Therapeutic window and ‘exposure’ If a drug is administered to a patient for months or year this means extensive ‘exposure’ If a drug is administered only briefly the exposure is low If the ADR is lethal any exposure may be unsafe: Moxifloxacin no longer used for bacterial infection as it has a small risk of causing a lethal cardiac syndrome, torsades de pointes Flecainide doubled mortality in the CAST study because of 1 year exposure unmasking unanticipated rare but lethal arrhythmia, VF Flecainide increases risk of spontaneous arrhythmia so it is not used if patients are taking it for a long time. 8  Therapeutic window and ‘exposure’ If a drug is administered to a patient for months or year this means extensive ‘exposure’ If a drug is administered only briefly the exposure is low If the ADR is non-lethal the exposure may be important: Guanethidine causes orthostatic hypotension that, though ‘mild’ is inevitable, meaning it cannot be used to treat hypertension A drug that causes a high incidence of flu-like symptoms may seem doomed – but COVID vaccines do this – acceptable because of one-off exposure (and the benefit is massive) Guanethedine can cause orthostatic hypotension so cannot be used to treat hypertension as hypertension medication has to be takne in the long term. For conditions that have very few symptoms like hypertension, side effects should be very few to zero as patients will not comply with taking the medication if they feel unwell when they didn’t before. 9  A therapeutic window therefore does not mean a therapeutic drug will have no ADRs The goal is a drug that can be used (to provide a benefit that outweighs any detriment) In a population, some detriment can be expected The role of SP is to mitigate against the risks of detriment The dose response relationship is key Population dose response relationships Therapeutic window Therapeutic effect Adverse effects Lethal effects Response (% of individuals) ED50 AD50 LD50 Drug dose Some adverse effects still seen in therapeutic window. 10  LD50 curve must be far away from the therapeutic window. The therapeutic window is not without ADRs Therapeutic window Therapeutic effect Adverse effects Lethal effects Response (% of individuals) ED50 AD50 LD50 Drug dose ADRs in humans fall into 5 types... Type A Dose-dependent; predictable from Main cause of known properties of the drug ADRs (~75%), rarely lethal Type B idiosyncratic response, not predictable, not Responsible for ~25% always dose related of ADRs, but majority of related lethal ones Type C long term adaptive changes Commonly occurs with some class of drug Type D Delayed effects e.g. carcinogenicity, Low incidence teratogenicity Type E Rebound effects following discontinuation of therapy Commonly occurs with some class of drug Which types may be predicted by nonclinical studies? All but B Breckenridge, A. (1996) Br. J. Clin. Pharmacol. 42, 53-8; Lazarou, J. et al. (1998) JAMA 279, 1200-5; 11  Type A generally caused by action on the drug target. Type B – not everyone gets this – genetic predisposition to the adverse effect. Type C and D – seen after a long time of taking the drug. Type D example – thalidomide causing birth defects. Types of acute ADRs ‘Supratherapeutic’ effect of interaction with the primary molecular target (‘augmented ADR’) (e.g. hypotension with an antihypertensive drug) Action on the primary molecular target expressed in non- target tissues (e.g. headache caused by glyceryl trinitrate) Secondary ADR = off target actions = actions on receptors etc that are not the primary molecular target (e.g. thyroid dysfunction caused by amiodarone) Non-specific effects (i.e., we don’t know the mechanism) ADRs caused by active metabolites Supratherapeutic = dose dependent Secondary = action on something other than the primary molecular target e.g. thyroid dysfunction caused by amiodarone – interferes with thyroid function as it contains iodine. E.g. active metabolite of codeine is morphine. 12  History of safety pharmacology ADRs originally examined by toxicologists (LD50 etc) In 1996 terfenadine was identified as having a liability for causing cardiac arrhythmias Very rare syndrome called torsades de pointes Ventricular arrhythmia, no cardiac output, rapidly lethal Drug used for innocuous condition (hay fever) Revelation that rare but lethal ADRs, especially (as here) mediated by off target effects (here, on cardiac K channel, not histamine H1 receptor) an unrecognized problem Not detected by conventional toxicological investigation and thousands of patients has taken drug before risk identified The ‘discipline’ of safety pharmacology thus invented LD50 = dose of drug needed to cause 5/10 animals History of Safety Pharmacology Pugsley MK, Authier S, Curtis MJ Principles of Safety Pharmacology Br J Pharmacol : 1382-1399, 2008 13  Regulatory requirements – ICH guidance ICH - International Conference on Harmonisation (of technical requirements for registration of pharmaceuticals for human use) Regulatory authorities of Europe, Japan and the United States Pharmaceutical companies follows guidance when seeking a license (e.g., from FDA in the US) for human use You require a license to test drugs in humans Priority = making safe medicines 14  ICH web page ICH S7A guidance covers 3 stated objectives To identify potential ADRs in nonhuman settings (e.g., hypotension in a rat) = Hazard Identification To evaluate potential ADR by toxicology assessment (nonclinical) and safety assessment (nonclinical and clinical) = Risk Assessment To investigate the mechanism of the adverse effects observed and/or suspected = Risk Management and Mitigation (minimisation) Identify hazards using non-human systems. 15  Risk assessment – look for effects in clinic and nonclinical. Find mechanism for what is going wrong. The laws require certain studies to be undertaken (‘regulatory’ studies) Candidat Pre-clin Target id Lead id Lead op Phase I Phase IIa Phase IIb Phase III Phase IV Launch e nom dev Regulatory toxicology Acute in vivo general toxicology In vivo genotoxicity and mutagenicity Chronic in vivo general toxicology Developmental and reproductive toxicology Carcinogenicity Regulatory Safety Pharmacology studies (see later) 16  ‘Attrition’ is when a drug in development ‘fails’ and is abandoned In the past, attrition was mainly do to lack of benefit: Poor pharmacokinetics, for example Or the molecular target not in fact useful Then the main reason for drug failure became ADRs So it made sense to detect the risk early in the discovery process Nature Rev Drug Discovery 3:711, 2004 Start out with thousands of compounds and get whittled down to one. Main reason for late failure is adverse drug effects. 17  Frontloading Target validation (part of ‘discovery’) is integrated with safety assessment at every stage of development Target Validation in Drug Discovery.... (‘Discovery’ tests proof of concept....) ‘Safety’ examines ‘Augmented ADR’ – on-target effects of supratherapeutic concentrations/doses And actions on the primary molecular target expressed in tissues other than the intended tissue Compound Safety in safety assessment This is about the drug itself Secondary (off target) ADR and metabolite ADRs Risk can be sought early by HTS frontloading and follow-up Non-specific effects Much harder to detect, especially since they may be human specific (especially with biologics such as monoclonal antibodies) Frontload safety assessment at every stage of development. Looking at supratherapeutic concentrations is an integral part of drug discovery. Apply drugs through high throughput screen to identify possibly secondary ADRs. 18  General considerations for Safety Assessment Some chemical structures are known to be associated with particular ADRs - ‘toxic pharmacophore’ If the drug class has benefit only when the toxic pharmacophore is present, this is called a ‘class effect’ Drug – Drug interactions (DDI) DDI: when one drug alters the rate or extent of absorption, distribution, metabolism or excretion, or effect of another drug This may increase ADRs of either drug e.g. cimetidine reduces the clearance of theophylline because theophylline is metabolised by cytochrome p450, and cimetidine inhibits p450 Class effect – similar structures cause similar effects. Consider what other drugs may be taken alongside the novel compound. Drug-drug – metabolized in same pathways. 19  Safety Pharmacological vs Toxicology historical distinction increasingly ADR assessment is managed by people in Safety Assessment toxicology is increasingly becoming very limited in scope Safety pharmacology only emerged when classical toxicology failed to identify the ADRs of terfenadine. 20  The distinction between Safety Pharmacology and Toxicology is quite arbitrary, and ‘territorial’. Increasingly all these functions will be Safety… Safety Pharmacology General Toxicology GLP and non-GLP Yes Yes Primary adverse effect type Type A Types C-E, (B) predicted Primary endpoints Functional responses/effects Gross clinical signs; histopathology Dosing regimen Single dose (usually) Chronic, repeat-dose Cardinal exposure parameter Cmax , PKPD modelling AUC (Area under curve) Sex of animals Usually Both Basis for risk assessment Margins NOAEL (No Adverse Effect Level) Statistical analysis Within animal pair wise Trend tests comparisons of means Study design Evolving discipline Established discipline Overall Objectives of Safety Pharmacology “To build Confidence in Safety (CIS)” by moving all attrition into the nonclinical phase of drug discovery To provide the data and guidance to help decisions to be made about the starting dose and range for Phase I (human) studies ICH S7A: Regulatory agencies require, as a minimum, nonclinical safety data for the 3 systems deemed critical for life: These studies, required by laws, are the ‘core battery’ To provide follow-up studies for mechanistic understanding of ADRs during clinical trials 21  Frontload safety pharmacology to find problems earlier on, build confidence in the safety of the drug and guide decision making for clinical trials. Core battery – core tests that need to be done on certain body systems. Key aspects of ICH S7A guidance Core battery and any supplemental follow-up must be conducted prior to first human exposure (FIH) Core battery should ordinarily be conducted to GLP Follow-up supplemental studies should be conducted to GLP ‘to the greatest extent feasible’ For in vivo studies, the clinical route of administration should be used where feasible The dose-relationship and time course of the ADR should be investigated Doses /concentrations should include and exceed the intended therapeutic range Human-specific metabolites should also be evaluated The same general principles also apply to the ICHS7B guidance FIH = first in human GLP = good laboratory practice. How does time course of ADR relate to exposure. Evaluate safety at higher than normal dosage because of risk of random factors that may increase blood concentration e.g. illness, drug-drug interactions, poor liver function etc. 22  Preclinical safety and discovery are designed to provide data to seek approval for FIH Experiment selection must be justified (necessary and sufficient) Guidance on follow up studies is somewhat subjective Selection should be based on what makes scientific sense When documents are prepared, the company must judge what is necessary and what is sufficient for FIH approval This involves a cost/benefit calculation Some S7A requirements may be disregarded for certain types of drug or intended use Trivial novelty, e.g., new salt having similar PK and PD to an established drug will not normally require full SP assessment No need for full SP assessment for locally applied agents (e.g., dermal) with low systemic absorption or exposure SP is almost irrelevant for agents for end-stage cancer, unless drug has a novel mechanisms of action For highly selective biologics, it may be sufficient to evaluate ADR as part of toxicology and/or pharmacodynamic studies For biologics that are a novel therapeutic class, or are not highly selective, SP studies may be required 23  Full assessment not needed if drug is similar to known drugs Safety pharmacology The Core Battery 1) Cardiovascular assessment 2) CNS assessment 3) Respiratory assessment CV assessment Blood pressure, heart rate and ECG intervals as a minimum, with inotropy a common extra Drugs that increase blood pressure are not tolerated for most therapeutic indications Even very small increases in blood pressure (5mmHg) over time cause increased incidence of stroke, coronary heart disease and heart failure Only chemotherapeutic agents – e.g. Sutent (sunitinib) – are permitted to increase BP 24  >5mmhg increase caused by drug = unlikely to be approved. CV assessment: Torsades de Pointes (TDP) Big issue for pharmaceutical industry Because TDP a rare but lethal ADR QT prolongation in vivo a good biomarker But this is slow and expensive Dog telemetry done just before FIH HTS sought (biomarkers) IKr screen (hERG) done GLP However IKr block does not always lead to TDP (ranolazine) QT prolongation tested just before FIH, done using repeat dose dog telemetry hERG = channel responsible for IKR current – does drug block this current? IKr block does not always lead to TDP. 25  Safety Pharmacology Part 2 [email protected] Many papers cited in these lectures are from J Pharmacol Toxicol Methods, which publishes an annual themed issue on safety pharmacology See also Pugsley MK, Authier S, Curtis MJ. Principles of Safety Pharmacology. Br J Pharmacol 154: 1382-1399, 2008 CV assessment: types of method Cell based Tissue based In vivo Cardiac ion chanels Whole heart, Purkinje Whole animal, e.g. rat*, e.g. IKr (hERG) fibre, ‘wedge’ prep dog monkey Patch clamp (manual Measures action Anaesthetised or or automated) potential conscious Measure block or ECG, haemodynamics opening of individual Complex measures e.g. ion channel organ blood flow *Never for TDP liability test Used together with discovery data to make an integrated risk assessment 26  Tissue based not standard, it is optional. It is done to see if there is anything to rule out. In vivo – wouldn’t use rats because they do not express the IKr channel so it is an irrelevant model. NO HERG SCREENING IN A RAT. Cardiovascular assessment in conscious telemetered animals Antenna Radio controlled Permanently implanted Left ventricular on/off switch Allows free roaming animals contractility Battery life 2 years continual use Reliable signal for BP and LVP Stable, consistent ECG Standard in dogs just before FIH BP and ECG electrode Now available for small animals Battery and electronics positioned in abdominal 5cm for early safety assessment muscle Standard to do repeat dose telemetry on conscious dogs. 27  Safety pharmacology The Core Battery 1) Cardiovascular assessment 2) CNS assessment 3) Respiratory assessment Lots of possible CNS ADRs From minor to lethal Lethargy Anorexia / weight gain Personality changes Sedation Dizziness Anxiety Drowsiness Nausea Disorientation Cognitive impairment Insomnia Sexual dysfunction Amnesia Involuntary movements Auditory dysfunction Motor in-coordination Depression Visual disturbance Tremor Autonomic effects Abuse potential Seizures Hallucinations Suicidal ideations etc… 28  CNS ADRs Most impact “quality of life” rather than “risk to life” But some are life-threatening: Decreased respiratory drive – respiratory arrest Decreased sympathetic outflow – cardiovascular collapse Loss of consciousness, seizures, convulsions Some are indirectly life-threatening: Drowsiness, cognitive impairment, motor inco-ordination, dizziness, visual disturbance – can affect e.g. driving performance Decreased respiratory drive = no prompt to breathe. Can happen with morphine. 29  Approaches to studying ADRs in the nervous system (applies to PNS as well as CNS) In vitro Neuronal cultures In vitro electrophysiology (ion channels; neurons; slices) Behavioural/neurological assessment Physiological recording (e.g. EEG; nerve conduction velocity) In vivo Biochemical recording (e.g. in vivo microdialysis; biomarkers) Imaging (e.g. MRI; MRS; PET; SPECT) mortem Histopathology Post (very much part of ‘toxicology’ …) CNS Safety Assessment Core battery Motor activity, behavioural changes, coordination, sensory/motor reflex responses and body temperature Done as ‘Functional Observation Battery (FOB)’ aka the modified Irwin's test (J Pharm Tox Methods 82:90-108, 2016) Follow-up Behavioural pharmacology, learning and memory, ligand- specific binding, neurochemistry, visual, auditory and/or electrophysiology examinations, etc. Irwin S (1968) Psychopharmacologia13: 222-57.3. Moser VC et al.(1997) Fund Appl Toxicol 35: 143-51; Redfern WS et al. (2005) J Pharm Toxicol Methods 52: 77-82. 30  Functional observational battery = range of tests that can predict whether or not there are CNS adverse effects. See below. Components of the FOB AUTONOMIC NEUROMUSCULAR salivation posture lacrimation gait piloerection body tone excessive urination grip strength diarrhoea/loose faeces tremor respiration shivering rectal temperature convulsions SENSORIMOTOR BEHAVIOURAL approach response arousal grasping reflex excessive vocalisation pupil response ease of removal touch response handling reactivity palpebral reflex stereotypy tail flick response bizarre behaviour startle reflex time to exit centre circle righting reflex line crossings landing foot splay rearing Also: any miscellaneous observations; overnight bodyweight gain post-dose 31  PK properties influence ADR risk e.g., The reason for the lack of sedation with second generation antihistamines is their low brain penetration Albeit, terfenadine has other issues... Yanai et al.(1995) Br. J. Pharmacol.116, 1649-55. Predicted brain penetration is used to reject compounds early Readily cross the blood- brain barrier: expect CNS Relatively poor ADRs penetration across the blood-brain barrier: thus: expect minimal CNS ADRs For “logBB+” drugs thus: FOB/Irwin Locomotor activity For “logBB-” drugs Seizure liability Abuse/dependence FOB/Irwin liability Follow-up tests (if Motor co-ordination? required) Cognitive tests? Redfern WS et al.(2005) J Pharmacol Toxicol Meth52:77-82. 32  Use pharmacokinetics to determine which follow up studied you need to do. FOB ‘hits’ may call for follow-up studies ADR Test(s) Motor co-ordination; dizziness Beam walking; rotarod; gait analysis Sedative/stimulant Locomotor activity; reaction time Proconvulsant Racine score, Pentylenetetrazol (PTZ); minimal electroshock seizure threshold (MEST); EEG Auditory dysfunction Acoustic startle Analgesia/hyperalgesia Tail flick; hot plate; thermal plantar test; paw pressure test Cognitive dysfunction Passive avoidance; water maze; operant methods Anxiogenic Elevated plus-maze Visual dysfunction Optometry; ERG; pupil control Abuse/dependence liability Withdrawal syndrome; drug discrimination; self-administration 33  24 hour continuous monitoring Methods to follow-up on motor co-ordination Beam walking Accelerating rotarod Gait analysis 34  Convulsion and seizure liability assessment Convulsion: Violent involuntary contraction or series of contractions of the voluntary muscles Tonic Prolonged contraction of the muscles Clonic Alternating contraction and relaxation of the muscles Seizure: Abnormal excessive or synchronous neuronal activity in the brain (detected on EEG) that may or may not progress to an outwardly visible effect (no convulsion) Prime animal to be sensitive to seizures Rodent models of seizure The most commonly used precipitants are drugs and electrical stimulation Drugs: usually pentylenetrazole Others include sound and shaking A convulsant compound is defined as lowering the threshold to the precipitant challenge Easter A et al.(2009) DDT14: 876-884. Both methods are declining in use...to be superseded by surrogate biomarkers, e.g., EEG measurements? 35  EEG (Electroencephalography) Mouse, rat or guinea-pig, dog, primate EEG telemetry device implanted under anaesthesia Recovery (several days) Recordings made in conscious, freely-moving animals Normal EEG Spike and wave EEG Baseline Ketamine 30mg/kg Hippocampal slice preparation (mouse, rat or guinea-pig), another surrogate method for seizure liability assessment Recording of population spikes from a hippocampal brain slice Control population spike Convulsant Drug Easter A et al.(2007) J Pharmacol Toxicol Methods56:223-233. Epileptiform population spike In vitro method to reduce need for and cost of live animals: 36  Record population spikes from hippocampal brain slices. There are patterns typical of seizures (epileptiform population spike). Drug dependence and abuse potential Regulatory Guidance: Non-clinical assessment of abuse potential is required for any compound that may have CNS actions 37  EMEA/CHMP/SWP/94227/2004 guidance document on dependence liability Tiered approach Before FIH: test if drug interacts with receptors known to be involved with abuse/dependence Before Marketing Authorisation Application: investigate withdrawal syndromes after repeat-dosing, self-administration, and drug discrimination studies (defined on next slide) Assessment of Abuse Potential Regulatory authorities recommend three studies: Drug discrimination Assess whether the subjective effects of a compound are similar to those of a known drug of abuse Self-Administration Will a compound initiate and maintain drug seeking and taking? Physical Dependence and Withdrawal Does cessation of chronic treatment (>2 weeks) result in a withdrawal syndrome? Moser P et al. (2011) J Pharmacol Toxicol Methods 63: 160-167. 38  Self-administration – does an animal try and self-administer more drugs? Rat Drug Discrimination Model Training phase Testing phase 39  Rat Drug Discrimination Model detects diazepam abuse liability Diazepam – patten similar to drugs of abuse. Drug self-administration 40  Physical dependence and withdrawal Important for CNS-active drugs Withdrawal symptoms in humans include: sweating, tremor, vomiting, anxiety, insomnia, and muscle pain In animals? Assess signs and symptoms following cessation of drug administration Physical dependency can result from CNS actions. Safety pharmacology The Core Battery 1) Cardiovascular assessment 2) CNS assessment 3) Respiratory assessment 41  Respiratory For non-inhaled drugs – effects on respiratory function: Plethysmography in conscious rats and also telemetry Effects on lung ‘pump’ function and gas exchange For inhaled drugs, in addition need to consider irritation, cough and toleration Models of cough are available Very few clinical ADRs are related to respiratory function Few drugs have respiratory ADRs Few drugs have respiratory adverse effects Free moving plethysmograph Chamber is semi-sealed Tidal volume & respiratory rate derived from change in volume Similar technique used in humans A very small signal, accuracy poor Any movement (sniffing, grooming etc) disrupts the signal, and animals need to be acclimatized to the chamber 42  Safety Pharmacology Other organ systems Why Assess the GI System? Vulnerable – we require to eat “Effects of the test substance on the gastrointestinal system should be assessed” A range of methods exist: 43  Not part of the core battery but should be considered for any oral drugs because of their interaction w ith the gastrointestinal tract. GI Safety Gastric emptying e.g. phenol red emptying Gastric acid secretion e.g. shay rat (ligated stomach model) Intestinal transit time e.g. charcoal meal 44  Integrated risk assessment How ‘safe’ should a drug be to be taken to human study? Depends on severity of disease (therapeutic target) And whether there are already useful therapies And severity of ADR And plasma level threshold for ADR (fold x therapeutic) Re Pr je ct oc ee d Modified from Redfern et al., (2002) Fund. Clin. Pharmacol., 16: 161-173; Valentin & Hammond (2008) JPTM 58:77-87 Integrated risk assessment example NCE targeted at Raynaud syndrome: existing therapy poor. NCE shows QT-prolongation in in vivo safety pharmacology studies at exposure ~10-fold the intended free therapeutic concentration. Decision: reject now or conduct human safety study for assessing proarrhythmia risk (ICH E14 “thorough clinical QT/QTc study”) Valentin & Hammond (2008) 45  Greater acceptable safety margin if there is no drug currently available. 46  It is all very well knowing how to validate a model But validation requires drugs with known human ADR liability If a disease has no useful therapies, or if the human liability of available drugs is uncertain (it will be if the ADR is rare) then it becomes very hard to validate the method (See Pugsley et al., 2008) Summary Safety Pharmacology, a rapidly emerging and evolving discipline, aims to predict human ADRs. It emerged via terfenadine, used widely, trivial indication, rare lethal ADR not anticipated by standard toxicology The ICH guidelines (S7A/B) on safety pharmacology enable a science-driven approach Good predictivity is achieved by good science –a step wise, logical progression through the preclinical and clinical phases, using validated and optimised tests Very few agents giving notable “Type A” adverse effects in the past would slip through the net of the present approach More next year (Dr Nandi’s course) Learning objectives: 47  By the end of this lecture by Dr Michael Curtis, students should be able to; Explain how the discipline of “Safety Pharmacology” came into being Describe how different forms of Adverse Drug Reactions are caused, especially the difference between type A and other types of adversity Describe how Industry and Regulators work towards mitigating against potential adversity Describe the “core battery” and some of the tests that are necessary for regulatory approval Explain what may trigger follow-up studies and how decisions to proceed to First in Human (FIH) studies are made 48