Pharma1922 Lectures Introduction to Pharmacokinetics (PDF)

Introduction to Pharmacokinetics (PK) and Pharmacodynamics (PD) Pharmacokinetics - What the body does to the drug, the study of drug absorption, distribution, metabolism and excretion Pharmacodynamics - What the drug does to the body, biochemical and physiological effects...

Introduction to Pharmacokinetics (PK) and Pharmacodynamics (PD) Pharmacokinetics - What the body does to the drug, the study of drug absorption, distribution, metabolism and excretion Pharmacodynamics - What the drug does to the body, biochemical and physiological effects of drugs, relationship between drug concentration and drug effect - Drug action Impact of Different Routes of Administration on Drug Disposition and Action - Different routes of administration and dosage form lead to different o Concentration- time profiles o Onset of action o Duration of therapy o Location of effect o Ease of administration o Cost - Is dependent on o Solubility o Stability o Availability - Action o Both biochemical and physiological effects o Dependent on drug reaching drug receptors Role of Pharmacokinetics and Pharmacodynamics in Drug Development and Medicines Regulation - Pharmacodynamics and pharmacodynamics are the main considerations in drug development - A drug must be safe (PK), effective (PD), non-toxic, be soluble etc. - Pharmacokinetics are the biggest reason why drugs do not make it to the market Affecting Drug Response - Pregnancy - Genetics - Obesity - Disease - Age - Drug interactions - Environmental factors - Drug adherence Absorption, Distribution, Metabolism and Elimination (Pharmacokinetics) Absorption - The process where a drug enters the bloodstream - Bioavailability is the measure of absorption, how much of the given drug makes it to the bloodstream, (a fraction) - Drug formulation, route of administration etc. can impact absorption - Incomplete or erratic absorption can lead to variability in drug effects Distribution - The process where a drug is spread across the body - The drug may go to certain organs, or bind to proteins in the blood serum - The volume of distribution (Vd), is a parameter used to measure the extent of distribution - Variations in tissue distribution, blood flow etc. can lead to a different pharmacological effect Metabolism - The process where a drug is chemically altered to make it more water soluble, facilitating elimination - Primarily done in the liver where enzymes like cytochrome P450 play a big role - Genetic variance in such drug metabolising enzymes can alter how an individual metabolises drugs - Can convert an active drug to an inactive form or produce active metabolites, which may have good or bad effects - A drug’s half life plays a part in metabolism Elimination - The process where a drug or its metabolites are removed from the body - Done mainly through the kidney (urine) or liver (bile and ultimately stool) - People with liver/kidney impairment fail to effectively eliminate drugs, meaning they may have drug accumulation, leading to an increased risk of toxicity - The rate of elimination is described by the drug’s half life - Clearance (Cl); volume per time, DOSE/AUC How Pharmacokinetics Informs the Use of Different Brands of a Medicine - If two drugs achieve the same drug concentration in the body they are considered bioequivalent - Absorption rate (Cmax) and the extent of drug absorption (AUC) are the main contributors to bioequivalence Pharmacokinetics Pharmacokinetics - Examines how drug concentration in different body parts is affected by route of administration, dosage form - Important in drug development, accumulation, toxicity, distribution, etc. - Has drug safety applications, therapeutic index (TI); toxic dose/ effective dose. Key Pharmacokinetic Parameters - Clearance (L/h) (elimination/excretion) o Efficiency of elimination of a drug o The irreversible elimination from circulation o Volume of blood cleared per unit time o Cl (L/h) = dose (mg) / AUC (mg*h/L) o Elimination rate (mg/h) = Cl total (L/h) * [Drug] (mg/L) - Volume of distribution (L,L/kg) (distribution) o The extent of distribution, not real o The amount of drug in the body to the plasma concentration o Back calculated from initial drug concentration plasma C0 following given IV dose o V = dose (mg) / C0 (mg/L) o Lipophilic drugs can traverse membranes ▪ Apparent Vd greater than 3L o Hydrophilic drugs are trapped in the plasma ▪ Apparent Vd approximately 3L - Half-Life (metabolism) o Time to halve the amount of drug in the body o Determined by clearance and volume of distribution o K = Cl/ Vd - Bioavailability (absorption) o Fraction of drug that gets absorbed o Compared against IV infusion which is 100% bioavailable o F= AUC/100  - C max (concentration max), T max (time at concentration max), AUC (area under curve) o Calculate AUC using trapezoidal rule, Area = (t2 – t1) x c2-c1 / 2 Single Oral Dose Plasma-Time Curve Rises when absorption is higher than elimination Cmax= when they are equal Falls when elimination is higher than absorption Single IV Dose Plasma-Time Curve First Order Kinetics Zero Order Kinetics When a constant proportion of the drug is eliminated When a constant amount of the drug is eliminated One Compartment Pharmacokinetics - Treat the body like one compartment (blood) - Curve has 1 phase Two Compartment Pharmacokinetics - Treat the body like two compartments - Second peripheral compartment (e.g. tissue) - Drug may not always distribute evenly and instantaneously throughout the body - May distribute unevenly across different tissues - Curve has 2 phases Three Compartment Pharmacokinetics - Third compartment may be bone Population PK Analysis - Doing blood tests on different people at different times and combining their data to 1 population - E.g. weight, sex, age, frailty, pregnancy - Women clear aspirin better than men Absorption Drug Movement Across Membranes - Drugs must cross cell membranes to be absorbed - Cell membranes have hydrophilic heads and hydrophobic tails Characteristics That Facilitate Movement - pH - Ionisation - Surface area LogP vs LogD - LogP describes a drug’s lipophilicity and predicts movement in cell membranes - P = [compound] organic/ [compound] aqueous - LogD also describes a drug’s lipophilicity - Aqueous phase is adjusted to a specific pH Transporters Involved in Drug Disposition - Peptides - Amino acids - Glucose - Aqueous diffusion – simple diffusion, concentration gradient - Lipid diffusion - Intestinal epithelia - Hepatocytes (liver) - Kidney proximal tubules - BBB Plasma Protein Binding - After absorption, some drugs are bound to proteins in the blood (plasma) - Proteins involved in the binding of drugs include o Albumin o Alpha-1-acid glycoprotein o Some lipoproteins - Only free drug can be distributed to tissues (drugs bound to protein cannot cross the cell membrane) Blood Brain Barrier - BBB o Endothelial cells of the capillaries o Basement membrane is continuous o Limited number of small, aqueous pores - Basically a lipid barrier - Lipid soluble drugs can dissolve in the membrane and enter the brain by passive diffusion - Water soluble drugs cannot enter the brain - BBB represents significant barrier to development of CNS drugs First Pass Metabolism - When a drug is swallowed it is absorbed from the stomach/ small intestine - Enters portal circulation and carried via portal vein to liver - Liver is the major organ for drug metabolism - If a drug has a high first pass metabolism, a higher dose is required - Avoiding first pass metabolism is considered a good thing - Sublingual, rectal, transdermal, injections avoid first pass metabolism, such routes of administration are absorbed into the veins which drain into the heart without entering the portal system (liver) Routes of Administration Oral - Convenient, relatively safe, no need for sterility - Affected by o Gut content (fed vs fasted) o Gastrointestinal motility o Splanchnic blood flow o Particle size and formulation Sublingual (under the tongue) - Convenient, relatively safe, no need for sterility, avoids first pass metabolism and acid/enzymes in the stomach, tastes important Eye Drops - Must be sterile, localised treatment e.g. eye infection, glaucoma Injection - Must be sterile, avoids first pass metabolism, faster onset of action, difficult to administer, adverse reactions, can be subcutaneous, intramuscular, intravenous Distribution Drug Distribution - For a drug to have any effect, it must be distributed to a site of action - Most drugs are distributed via passive diffusion - Lipophilic drugs can traverse membranes - Hydrophilic drugs are trapped in the plasma - Factors that affect drug distribution are o logP, between 0 and 5 is good o Molecular weight, less than 500 is good o Water solubility o Lipid solubility o Molecular size of water-soluble drugs o Whether the drug is carried by transporters o Protein binding o Blood flow to the tissue o Specialised barriers within the body e.g. BBB Volume of Distribution (Vd) - Body water is divided into 3 distinct groups o Plasma (3L) o Interstitial (9L) o Intracellular (28L) - Lipophilic drugs can traverse membranes (Vd>3L) - Hydrophilic drugs are trapped in the plasma (Vd=3L) Tissue Affinity - Some drugs accumulate in certain tissues or cell types for which they have affinity - Drugs with an affinity for plasma proteins remain in the blood longer - Drugs with an affinity for melanin remain in pigmented tissues for longer etc. Metabolism Drug Metabolism - Increases the water solubility of a drug facilitating elimination - The liver is the main drug metabolising organ - Occurs via faeces or urine - While it facilitates elimination it may also increase toxicity or pharmacological effect - Metabolism results in metabolites, they are less active and more water soluble (polar) than the parent compound Phase I Metabolism Reactions - Catabolic - E.g., oxidation, reduction and hydrolysis - Occurs mainly in the liver - It is the chemical conversion of a chemical into something more water soluble (polar) - Cytochrome P450 enzymes are the main enzymes involved in phase I reactions, CYP450 - Different CYPs metabolise different drugs - Sometimes the drug is metabolised to be more toxic, sometimes to be more pharmacological - Some drugs are inactive until they have been metabolised - E.g. codeine o Converted to morphine by CYP2D6 o Genetic polymorphisms exist, some will have poor analgesic effect, others will have opioid effect o Dependent on race, genetics Phase II Metabolism Reactions - Anabolic/ conjugation - Making the molecule bigger and more polar; more likely to be excreted - Polar group is attached to the drug by a “handle” - E.g., glucuronidation, sulphation, glutathione, acetylation - Glucuronidation o Most common phase II o Catalysed by UGTs - Glutathione o In the liver o Non-enzyme o For paracetamol metabolism, paracetamol overdose Excretion and Elimination Renal Elimination/Excretion - Glomerular filtration o Removal of free drug at the glomerulus o Important for most drugs o Only molecules small enough will pass through filtration slit - Active tubular secretion o Energy dependent process by which drug is transported into urine o In proximal tubule o Subject to competition by drugs with same charge o High elimination rate o E.g. penicillin - Tubular reabsorption o Passive process in which drug in urine diffuses back into blood o Drug must be uncharged o Drug gets concentrated in urine, then follows gradient back out into blood - Affected by pH of the urinary matrix, you can alter your own pH o Ammonium chloride for acidification o Sodium bicarbonate for alkalinisation - If drug is unionised, it can cross cell membranes and will be reabsorbed - If drug is ionised, it will be trapped in filtrate and excreted in urine - Fraction unchanged (fu), an fu of 1 implies a drug which has been totally cleared, renally unchanged ▪ Fu = renal clearance / total clearance - Estimate renal clearance through urine samples and noncompartmental estimation Faecal Elimination - Drugs appear in faeces by two major mechanisms o By not being absorbed into systemic circulation o By being absorbed, excreted in bile and deposited back into small intestine - Bile o Excretes cholesterol o Absorbs lipids o Stimulates intestinal motility o Produced in liver and stored in gall bladder Enterohepatic Recycling - Reabsorption of drug or metabolite, bile excreted and reabsorbed by small intestine, returned to liver - May produce a secondary therapeutic effect Pulmonary Elimination - Elimination of gases via the lungs - E.g. alcohol Breast Milk Elimination - Small unionised drugs Sweat - THC, cocaine, morphine Hair - Amphetamines Saliva - Antiepileptics, amphetamines Pharmacodynamics Pharmacodynamics is what the drug does to the body - The relationship between drug concentration and effect - Drugs are also called; ligand Drug Actions - A drug must bind to one or more cell constituents to produce a pharmacological response - The drug and its binding site must be complimentary o Charge attracts the drug to binding site o Active site is called the orthosteric binding site - These sites include o Receptors ▪ Protein sensors for chemical communication ▪ Macromolecular complex which binds to a drug with high specificity o Ion Channels ▪ Protein molecules that permit flow of specific ions along their concentration gradient Target Mechanism ▪ Two types Receptor Agonist or Antagonist Ligand-gated ion channels Ion Channels Blocker or modulator Voltage-gated ion channels Transporter Uptake inhibitors ▪ Either blockers or modulators Enzymes Inhibitor o Transporters ▪ Aka carrier molecules ▪ Allow the movement of ions against their concentration gradient o Enzymes ▪ Decreases the energy required for a chemical reaction - Once the drug has bound, the effect on a particular system can be: o Activating e.g. agonist o Enhancing e.g. positive modulator o Attenuating e.g. negative modulator or inverse agonist o Interfering e.g. antagonist: no effect on receptor itself but lowers response to other agents Orthosteric and Allosteric - Orthosteric binding site o Recognition site of the endogenous molecule on the receptor, agonists and antagonists bind here - Allosteric binding site o The “other” binding site on the receptor, modulators bind here Drug Binding - Generally, the bonds between a drug target and receptor are weak and reversible o Ionic bonds o Hydrogen bonds o Dipole o Van der Waals force o Sometimes covalent Affinity - Refers to the drugs ability to bind to the target, strength of relationship between ligand and cell constituents - Quantified as concentration of drug required to occupy 50% of target proteins o Drugs with higher affinity only need a very small concentration to bind to the target. - A drug can have affinity for more than one target, it can bind to more than just one type of protein o But it can only bind to those targets for which it has affinity Selectivity - Ability of a given drug concentration to produce one effect over another (e.g. therapeutic effect over side effect) - For a drug to be effective it must act selectively at a particular target, no drug is entirely specific to a target, hence why we get side effects - Since drugs are likely to have higher affinity for some targets compared with other, we can choose a concentration of the drug that binds to one target but not others, is selective for a particular target over other targets at the concentration chosen - Selectivity is concentration-dependent, as you increase concentration you increase the probability for the drug to bind to other sites Intrinsic Efficacy - Measure of the ability of a drug to elicit a response - Defined as the maximal effect a drug can produce on a specific tissue, expressed as a proportion of the maximal effect of a full agonist on that tissue o Full agonists = intrinsic efficacy = 1 o Partial agonists = intrinsic efficacy = 0 to 1 o Antagonists = intrinsic efficacy = 0 o Inverse Agonists = intrinsic efficacy = Raf -> MAP - Jak/Stat pathway o Involved in response to cytokines o Phosphorylated stat migrates to nucleus and activates gene expression o Jak -> stat - Kinase inhibitors are drugs that stop phosphorylation occurring, helpful in cancer o 7 different types o Type I, interacts with active conformation of kinase, e.g. crizitonib o Type II, targets DFG loop (inactive), e.g. imatinib o Type III, bind to a site in the ADP pocket (deep), e.g. trametinib o Type IV, substrate directed inhibitors (allosteric), e.g. everolimus o Type V, bivalent irreversible inhibitors (allosteric), e.g. N/A o Type VI, covalent binders (permanent), e.g afatinib o Type VII, nonclassical allosteric inhibitors, e.g. SSR128129 Corticosteroids (adrenal system) - Hormones produced by the adrenal system - Produced as drugs for their anti-inflammatory and immunosuppressive properties - Adrenal system (two systems) o Inner Medulla ▪ Catecholamines e.g. dopamine o Outer Cortex ▪ Aldosterone ▪ Testosterone ▪ Glucocorticoids - Glucocorticoids o Carbohydrate and protein metabolism ▪ Increase glucose production ▪ Increase glycogen storage ▪ Decrease uptake and utilisation of glucose ▪ Decrease protein synthesis = increased protein breakdown = tissue wasting ▪ Reduces calcium absorption in GI tract = osteoporosis o Anti-inflammatory actions ▪ Decreases release of neutrophils from blood vessels ▪ Decreases activation of T-helper cells o Too much glucocorticoids = Cushing’s syndrome o Too much mineralocorticoid =Conn’s syndrome o Not enough glucocorticoids = Addison’s disease ▪ Glucocorticoid replacement therapy Cancer - Uncontrolled cell growth - Caused by mutations in DNA which control cell growth and division o Grows in absence of signals o Ignores signals for stopping division or apoptosis - Genes affected o Proto-oncogenes o Tumour suppressor genes o DNA repair genes - Treatments o Cytotoxic drugs ▪ E.g platinum o Kinase inhibitors ▪ E.g. imatinib o Monoclonal Antibodies ▪ E.g. rituximab o Immune Checkpoint Inhibitors ▪ New and upcoming ▪ Tricks the immune system into turning itself off (make cancer cells kill themselves) Overview of Preclinical Pharmacology Pre-Clinical Pharmacology - Drug Discovery o Chemical synthesis, formulations, identifying the lead drug - Pre-Clinical in vitro testing o Molecular, cellular or organ testing - Pre-Clinical In vivo testing o Testing in animals Core Framework Pharmacodynamic Profiling - Done in vitro or in silico - Requires good understanding of normal physiology or pathology of the drug’s function - E.g. o Testing organs in organ baths o Bruton tyrosine kinase inhibitor – cancer drug - Following a positive result in vitro, we move onto animal testing (in vivo) o Does the drug do what it did in vitro o Does the drug reach the target o Do we use a healthy/sick animal, old/young etc. o A lot of considerations ▪ Mode of Action ▪ Selectivity ▪ Specificity Pharmacokinetic Profiling - Considerations o Toxicity, safety, dosing regimens, route of administration, starting dose o Must think about ADME Drug Regulation Regulatory System in Australia - Since 1958 there has been regulation in Australia - TGA is currently the biggest player, updated regularly since its inception 1989 - Since the 1990s the biggest changes have been to allow for more streamline drug approval - Therapeutics Good Act o Underpinned by regulations, orders, laws, guidances and standards o Provide a national framework for the regulation of therapeutic goods so as to ensure their quality, safety, efficacy and timely availability o Established the TGA o Established the ARTG o Applies to all therapeutic goods o Licensing of medicines o Importing of medicines etc. o Pre market evaluation o Post market surveillance/ maintenance o Risk based approach to regulation Therapeutic Goods - A good which is represented in any way to be, or likely to be taken to be, for therapeutic use o Prescription medicines o OTC medicines o Complementary medicines o Sunscreen o Medical devices o Biologicals o Blood and blood components - All therapeutic goods must be on the ARTG to be supplied in, imported to or exported from Australia Pre-Market Evaluation - Rigorous trialling, Phase I to IV etc., classification/scheduling, dossier, ARTG approval, market - Engagement between authorities and drug companies Post Market Product Maintenance - Continuous monitoring for identification of safety issues - An effective system to report any safety concerns - TGA checks to ensure ongoing adherence to safety standards Future Directions of Drug Design and Discovery Cryogenic Electron Microscopy (Cryo-EM) - Allows for the determination of large protein structures, specifically membrane proteins - Method o A sample of the membrane is embedded in a “nano disc”, which acts as the cell membrane o The chamber is cooled down to 4K o The membrane is coated in a very thin layer of ice o Electron beams bombard the membrane o The results are collected and a 3D map of the protein is made - Protein structures of full length are produced, enables visualisation of antibodies which was previously difficult Molecular Dynamics - Simulation of atoms over a time, not just a picture - Considerations o Bonded energy ▪ Covalent bonds ▪ Bond angle, length o Non-bonded energy ▪ Electrostatics ▪ Van der Waals o Temperature o Pressure - Method o Minimise energy o Equilibrate the system o Simulation, on GPU - Used for o Ligand binding affinity ▪ Docking score o Binding site determination ▪ Best binding site Artificial Intelligence (Alphafold) - The way that proteins are built follow fundamental rules of nature, if AI knows this it can predict protein structure - First alphafold was poor, alphafold 2 was good - Method o Takes protein sequence from databases o Develop a multiple sequence alignment o Data is processed and informs bond angles o A “relaxed” 3D image is produced - Used for o Proteins that are impossible to characterise in vitro - Limitations o Cannot predict ligand and apo states o Cannot predict DNA or RNA o Struggles to predict whether ion channels are opened or closed o Need supercomputers Organ on a Chip (OoC) - Tissue models based in microfluidic chips, mimic human physiology - Include tiny channels which allow for the uptake of small volumes - Drugs or other compounds can be added to test the response from cells Personalised Medicine - Using a person’s genetic information to inform prevention, diagnosis and treatment of disease - E.g. o Imatinib ▪ Patients are screened for a mutation, if they have it, they are given imatinib treatment, cancer Safety and Toxicology Drug Toxicity Categories - Pharmacophore based toxicity o Primary pharmacology of the agent o What does it actually do - Chemotype based toxicity o Structural features or physiochemical properties o Noncovalent bonding interactions - Metabolism based toxicity o Some drugs harbour toxic metabolites Safety Studies to Detect Toxicity in Pre-Clinical Phase - Single Dose Toxicity o 2 mammalian species, at least 1 non rodent o One route is the proposed clinical route, second route is parenteral o Dose should exceed the anticipated clinical dose, main source of PK data - Repeat Dose Toxicity o Detect longer term chronic effects o Generally, just the proposed clinical route o Dose should be up to maximum tolerated dose - Genotoxicity o Bacterial mutation (Ames) test, in vitro and in vivo o OR o Bacterial mutation (Ames) test, in vivo test for genotoxicity with two different tissues - Carcinogenicity o Rat or mouse o Given drug daily, orally at differing doses o Animal is examined for weight gain, clinical signs, tumour incidence - Reproductive toxicity - Safety pharmacology - Pharmacokinetics studies Reasons for Withdrawal from Market - Hepatic; hepatic failure, liver injury - Cardiovascular; stroke, arrythmia - Neurological; neurotoxicity, depression - Renal; renal failure - Etc. etc. Adverse Drug Reactions Augmented Adverse Drug Reactions (Type A) - Dose related - E.g. digoxin o Narrow therapeutic index o Administered orally or IV o Absorption from stomach and upper small intestine (80%) o 20% bound to plasma proteins ▪ Symptoms Lethargy Confusion GI symptoms Impaired vision Cardiac arrythmias o Digoxin toxicity is prevented by tailoring dosage to ▪ Renal function ▪ Clinical response ▪ Concentration monitoring o Digoxin toxicity is treated by ▪ Antidote (digifab) Bizarre Adverse Drug Reactions (Type B) - Not dose related - Hypersensitivity reactions - Type I o Immediate and rare o E.g. anaphylaxis, hives - Type IV o Delayed and more common o E.g. rashes, Steven Johnson Syndrome - E.g. sulphonamide; o fever, dyspnoea, cough, rash, Steven Johnson Syndrome Chronic Adverse Drug Reactions (Type C) - Dose and time related, using too much for too long - E.g. corticosteroids o Used for patients with adrenal failure o Anti-inflammatory/immunosuppressive therapy o Adverse reactions ▪ Adrenal suppression due to suppression of corticotrophin sectretion ▪ Oral candidiasis due to weakening the immune system in the mouth and throat Delayed Adverse Drug Reactions (Type D) - Time related, take long time to manifest - Teratogenesis (causes birth defects) o E.g. ▪ Thalidomide Originally a tranquiliser Marketed as reducing anxiety, tension and morning sickness Never tested on pregnant women Children had horrible birth defects - Carcinogenesis (cancer) o E.g. ▪ Smoking End of Use Adverse Drug Reactions (Type E) - Abrupt cessation of drug where there is physical dependence may lead to withdrawal syndrome - Dependence comes from repeated administration of a drug - Physical dependence- when withdrawal of the drug will cause adverse physiological effects - E.g. o Opioid withdrawal; crying, sweating, yawning, anxiety, restlessness, GI issues o Benzodiazepine withdrawal; anxiety, dysphoria, irritability, sweating, insomnia o Alcohol withdrawal; - Withdrawal is managed by medical (substituting drugs) and psychological care (behaviour management) Failure of Therapy Adverse Drug Reactions (Type F) - Failure of therapy due to insufficient drug o Enzyme inducers decreasing exposure to therapy o Prevention of absorption from gut o Overly cautious administration of chemotherapy - E.g. contraceptive pill o Lower dose meant less side effects o CYP3A4 – increases rate of metabolism – reduces plasma concentration of pill – reduces efficacy – pregnancy Clinical Trials Methodological Approaches to Understanding the Efficacy and Toxicity of New Drugs in Humans - Pre-clinical Analysis o Confirm good PK properties o Confirm mechanism of action in vitro and in vivo, identify biomarkers of response - Safety Analysis o Complete full toxicological assessment in 2-3 animal species o NOAEL calculations in 2-3 animal species o Determine safety factor o Calculate MRSD Clinical Trials - Intervention studies (I,II,III and IV) OR descriptive studies (case reports/studies, cohort studies) - Confirm absence of toxicity and establish efficacy - Identify Type A (augmented) adverse reactions – dose related - They are either o Preventive ▪ Where patients are disease free ▪ Does drug reduce risk of developing disease ▪ E.g. IBIS II trial – breast cancer prevention o Therapeutic ▪ Where patients have disease ▪ Dose drug reduce mortality due to disease ▪ E.g. salmeterol reduce bronchoconstriction in asthmatic episodes Phase I – will it harm the patient – safety - Testing an experimental drug on sick patients or healthy volunteers, up to 100 people - Open label, single arm study - Testing different doses sequentially - Identify toxicity, side effects, safe and effective dosage, pharmacokinetics, route of administration (oral, IV, inhalation etc.), dosage frequency, mechanism of action - Informs phase II - 50% of drugs have failed by now – not safe Phase II – will it make the patient better – safety + efficacy - Testing effectiveness on sick patients, up to 1000 patients - Open label, single arm study OR double blind, randomised, placebo trial - Measure treatment response, beneficial physiological change - Identify a confirmed efficacy, - Informs phase III - 66% of drugs have failed by now – do not do what they need to do Phase III – is it better than existing treatment - efficacy vs. existing treatment - Testing if it is better than existing treatments, 1,000 to 10,000 people with defined condition - Double blind, randomised clinical trial, drug vs existing drug vs placebo - It is randomised to reduce bias, random error, population variability - Identify that mechanism of action matches phase II data, no type A ADRs, better and/or safer than existing drug - Informs phase IV - 75% of drugs have failed by now Phase IV – does it work in the community – safety, efficacy - >10,000 people with the disease are given the drug in off label prescribing - Usually after the drug is approved - Further evaluation of long-term safety and effectiveness, serious ADRs - Post approval safety - Most of such systems require voluntary reporting,