Introduction to Drug Discovery & Development PDF Notes
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These are notes on drug discovery and development. Topics covered include pharmacology, pharmacokinetics, pharmacodynamics, and the drug development process. The pharmaceutical industry, FDA regulations, drug toxicity, personalized medicine, and the role of clinical trials are also discussed.
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Week 1: Introduction to Drug Discovery & Development Learning Objectives: - Basic drug characterization (ex. Potency, EC50, IC50, efficacy, selectivity, ADME) - Difference between pharmacokinetics and pharmacodynamics - PK/PD differences in geriatric patients -...
Week 1: Introduction to Drug Discovery & Development Learning Objectives: - Basic drug characterization (ex. Potency, EC50, IC50, efficacy, selectivity, ADME) - Difference between pharmacokinetics and pharmacodynamics - PK/PD differences in geriatric patients - The role of Pharmacogenetics in drug response - The role of the FDA in drug discovery - The importance of risk/benefit assessment in drug development - Historical events that led to FDA regulations I. Key Definitions in Pharmacology A. Pharmacology:the study ofdrug interactions withliving systems B. Pharmacokinetics (PK): what the body does to the drug(Absorption, Distribution, Metabolism, Excretion - ADME) C. Pharmacodynamics (PD): what the drug does to the body(mechanism of action) D. Pharmacogenetics:howgeneticsaffect drug responses E. Toxicology: study ofadverse effects of drugs & poisons F. Agonist: activates receptors(ex. nicotine) 1. Partial agonist:activates, but not fully 2. Inverse agonist:lowers receptor activity below baseline G. Antagonist: blocks receptor activation(ex. antihistaminesblock histamine receptors) II. Pharmacokinetics (What the Body Does to the Drug) A. Routes of Drug Administration 1. Oral (pills, syrups): slowest but safest(first-passmetabolism in liver) 2. Sublingual (under the tongue): fast absorptionintothe blood 3. Inhaled (lungs): very fast(15 sec to brain, usedfor asthma) 4. Parenteral (IV/injection): fastestbutmost dangerous 5. Topical (ointment/creams): localized effect 6. Transdermal (Patches): slow, steady absorption 7. Rectal/Vaginal: used whenoral is not possible(ex.nausea) B. ADME 1. Absorption: a) Drug enters bloodstream b) Factors affecting absorption: (1) Molecule size, charge, solubility, pH, food presence (2) Larger surface area = better absorption(ex. Intestines> stomach) 2. Distribution a) Drug moves through blood to target tissues b) Water-soluble drugsstay in the plasma ) Lipid-soluble drugspenetrate tissues easily c 3. Metabolism (Liver): a) Liver enzymes (CYP450 system) break down drugs b) First-Pass Metabolism: (1) Oral drugpartially destroyed in liver before reaching the bloodstream (2) Explains whyIV drugs have stronger effects than oral drugs 4. Excretion: a) Kidneys (Urine) & Liver (Bile/Feces)remove drugsfrom the body b) Incomplete excretion leads to drug accumulation (toxicity) III. Drug Metabolism & Kinetics A. First-Order Kinetics (Most Drugs) 1. Metabolism rate is proportional to drug concentration 2. Constant fraction (50%) eliminated per pass through liver 3. Half-life (t1/2):time required for50% of drug tobe eliminated B. Zero-Order Kinetics (Alcohol, Aspirin) 1. Metabolism is constant, regardless of dose 2. Higher overdose risk(ex. Alcohol: fixed metabolismrate) IV. Geriatric Pharmacology & Risks A. Elderly take 31% of all prescribed drugs in the U.S. B. Increased sensitivity & variabilityto drugs due to: 1. Decreased metabolism and excretion 2. Increased body fat (affects lipid-soluble drugs) 3. Decreased total body water (affects water-soluble drugs) 4. Reduced serum albumin (increased free drug concentration) 5. Altered receptor sensitivity (ex. Beta-blockers less effective) C. Polypharmacy (multiple drugs at once) = high risk for drug interactions D. Adverse Drug Reactions (ADRs) in Elderly 1. 7x more likelythan younger adults 2. 50% of all medication-related deaths 3. Common ADRs: a) CNS depressants (confusion, sedation) b) Anticoagulants (bleeding risk) c) Alpha-blockers (hypotension) d) Anticholinergics (urinary retention, blurred vision) V. Pharmacogenetics & Drug Response Variability A. Genes affect drug metabolism & efficacy B. CYP2D6 Enzyme Example: 1. Low CYP2D6 activity -> poor codeine metabolism -> no pain relief 2. High CYP2D6 activity -> ultra-rapid metabolism -> morphine overdose C. E nvironmental factors (smoking, pollution, diet) also affect drug metabolism VI. FDA & Drug Regulation A. FDA ensures drug safety and efficacy B. Key Drug Regulations: 1. 1906 Pure Food & Drug Act:prevented misbranded drugs 2. 1938 Food, Drug, & Cosmetic Act:required drug safetytesting (after sulfanilamide disaster) 3. 1951 Durham-Humphrey Amendment: differentiatedOTCv Prescription drugs 4. 1962 Kefauver-Harris Amendment:requiredproof ofdrug efficacy & stricter safety testing(after thalidomide tragedy) 5. 1984 Hatch-Waxman Act:created moderngeneric drugapproval process VII. Drug Toxicity & Risk-Benefit Analysis A. All drug are poisons; dose determines toxicity B. Maximum Tolerated Dose (MTD): highest safe dose before toxicity C. Risk-Benefit Ratio: balances therapeutic effect v. side effects D. Clinical Trials: test drug safety and efficacy before FDA approval VIII. Final Takeaways A. Pharmacokinetics (ADME) explains how drugs move through the body B. Elderly patients have altered drug metabolism, increasing risk of ADRs C. Pharmacogenetics helps personalize medicine for better outcomes D. FDA regulates drugs to ensure safety and efficacy E. Risk-Benefit Analysis determines if a drug is worth the potential side effects Week 2: History of Drug Development Learning Objectives: - Describe key discoveries that shaped the modern pharmaceutical industry - Identify biotech breakthroughs that transformed disease treatment - Discuss challenges & societal issues in 21st-century drug discovery I. The Origins of Drug Discovery A. Isolation of Pure Substances 1. Early 19th century:drug development began by extractingpure substances fromplantsusingsolvent extraction techniques 2. Key shift:from folk medicine toexperimental chemistryand scientific drug formulation B. Early Drug Discovery Milestones 1. Aspirin: The First Synthetic Drug a) Hippocrates (Ancient Greece)usedwillow tree barkfor pain relief b) J ohann Buchner (1829):isolatedsalicinfromMeadowsweet (spiraea ulmaria) c) Fleix Hoffman (1898, Bayer):modifiedsalicylic acid-> acetylsalicylic acid (Aspirin) to reduce stomach irritation d) March 6, 1899:Bayer patentsAspirin, now one of themost widely used drugs globally (50+ billion pills/year) 2. Morphine & Opioids (19th Century) a) Alexander Wood (1853):invented thehypodermic syringe, makingmorphine injectionpossible b) Morphine revolutionized pain managementbut led to widespreadaddiction c) Diacetylmorphine (Heroin) was synthesized from morphine but later found to behighly addictive d) Today:opioids (ex. oxycodone, fentanyl) are essentialfor pain but contribute to opioid crisis 3. Malaria Treatment & Quinine (17th-19th Century) a) Jesuits (1600s):usedcinchona tree barkto treatmalaria b) 1820: Quininewas isolated byPelletier & Caventou,making treatment more effective c) R.B. Woodward (1944):synthesizedquinine, advancingorganic chemistry & pharmaceutical synthesis d) Today: Quinine derivatives likechloroquine and mefloquineare still used, butresistance is a challenge II. Major 20th-Century Drug Discoveries A. 1900-1910: Epinephrine (Adrenaline) 1. Trade Name:Adrenalin (Parke, Davis & Co,) 2. Uses:treatscardiac arrest, anaphylaxis, asthma,sepsis 3. Today:still used inemergency medicine and localanesthesia B. 1909: First Rational Drug Design (Salvarsan for Syphilis) 1. Paul Ehrlich & Sacachiro Hata:developedarsphenamine(Salvarsan), the firstsynthetic antimicrobial 2. Goal: maximizetoxicity to the pathogenwhileminimizingtoxicity to humans 3. Replaced by penicillin in 1944 C. 1922-1982: Insulin & Diabetes Treatment 1. 1922: insulin extracted from animals(first successfuldiabetes treatment) 2. 1978: recombinant DNA insulinwas produced usedE.coli(Genentech & Eli Lilly) 3. 1982: Humulinbecause the firstFDA-approved geneticallyengineered drug 4. 2014: Afrezza inhalable insulinwas introduced D. 1935: Sulfonamides (First Effective Antibiotics) 1. Trade Name:Prontosil -> metabolized intosulfanilamidein the body 2. S aved thousands of lives, including Winston Churchill & Franklin Roosevelt Jr. 3. Still used today(ex, sulfamethoxazole-trimethoprim) E. 1942: Penicillin- The First Mass-Produced Antibiotic 1. Discovered by Alexander Fleming (1928) 2. Mass production enabled by WWII efforts 3. Transformed medicine, drastically reduced deaths from infections F. 1957: Antipsychotics & Thorazine (Chlorpromazine) 1. First drug to treat schizophrenia 2. Revolutionized psychiatrybut had severe side effects 3. Today: Atypical antipsychotics (ex. Clozapine, Risperidone) are more widely used G. 1960: Birth Control Pills (Oral Contraceptives) 1. Trade Name:Enovid 2. Combination of estrogen (mestranol) and progestin (norethynodrel) 3. Today:many formulations exist, includingtransdermalpatches and intrauterine devices (IUDs) H. 1967: Beta-Blockers (Propranolol) 1. Developed by James W. Black 2. First drug to treat high blood pressure and heart disease by blocking adrenaline 3. Still widely used today I. 1981: ACE Inhibitors for Hypertension (Captopril) 1. First effective treatment for high blood pressure 2. Still a key medication for heart disease today J. 1987: Antidepressants- Prozac (Fluoxetine) 1. First Selective Serotonin Reuptake Inhibitor (SSRI) 2. Still widely prescribed for depression and anxiety disorders K. 1997: Cholesterol-Lowering Drugs (Statins) 1. Trade Name:Lipitor (Atorvastatin) 2. Revolutionized heart disease prevention by lowering LDL cholesterol 3. Newer drugs (PCSK9 inhibitors) can reduce cholesterol by 60% L. 1997: HIV/AIDS Treatment- Saquinavir (First HIV Protease Inhibitor) 1. Revolutionized HIV treatment, turning it from a fatal disease in a manageable condition 2. Modern drugs (ex. Descovy, Biktarvy) provide even more effective treatment M. 1998: Erectile Dysfunction Treatment- Viagra (Sildenafil) 1. Originally developed for heart disease, found to treat ED 2. First phosphodiesterase (PDE5) inhibitor, widely used today N. 1998: Targeted Cancer Therapy- Gleevec (Imatinib) 1. First drug to specifically target cancer mutations (chronic myeloid leukemia) 2. T ransformed cancer treatment with fewer side effects than chemotherapy III. 21st Century Innovations in Drug Development A. 2014-Present: Hepatitis C Cures 1. Sovaldi, Harvoni, Epclusa, Mavyret -> 90% cure rates for Hepatitis C 2. Costly ($84K+ per treatment), sparking debates on drug pricing B. Ketamine for Depression (2019) 1. Originally an anesthetic and recreational drug 2. Recently FDA-approved for treatment resistant depression C. Gene Therapy & CRISPR (2023) 1. First FDA-approved CRISPR-based gene therapy (Casgevy for sickle cell disease) 2. Gene therapies also approved for rare blindness, cancer, and inherited disorders IV. Final Takeaways A. Modern medicines evolved from natural remedies to synthetic drugs and biotech innovations B. Landmark discoveries (aspirin, Insulin, Penicillin) shaped the pharmaceutical industry C. Drug design shifted from trial and error to rational drug design and genetic engineering D. Breakthroughs in cancer, HIV, heart disease and mental health continue to transform healthcare E. Gene therapy and precision medicine represent the future of drug development Week 3: Nature of Disease Learning Objectives: - Define disease and its key components - Understand patterns of disease (ex. endemic, pandemic) - Explain the immune system’s role in health - Differentiate between infectious and non-infectious diseases - Understand pharmacokinetics v. pharmacodynamics - Recognize the significance of geriatric pharmacology and pharmacogenetics I. What is Disease? A. WHO Definition:health is astate of complete physical,mental, and social well-being, not just the absence of disease B. Disease: interruption of normal bodily functionsdueto internal or external factors C. Deviation from normality is not necessarily a disease 1. Example: mild atherosclerosis in 50 yr olds or osteoporosis in postmenopausal women are not considered disease but are often treated II. Types of Disease A. Infectious Diseases 1. Caused by pathogens(bacteria, viruses, fungi, parasites) 2. Spread via direct or indirect contact 3. Example:TheBlack Death (Bubonic Plague, 1347-1700s) a) Caused by Yersinia pestis b) 60% fatality rate c) Spread via fleas and lice (not bad air, as once thought) d) Controlled through quarantine (40-day isolation period) B. Non-Infectious Disease 1. Caused by genetics, environment, or lifestyle 2. Not transmitted person-to-person 3. Examples: a) Diabetes, cardiovascular disease, osteoporosis b) Alzheimer’s, Parkinson’s, depression III. Patterns of Disease A. Endemic:consistently present in a population (ex.malaria in Africa) B. Epidemic:rapidincrease in cases in ashort time(ex. Ebola outbreak) C. Pandemic: global spread(ex. COVID-19) D. Sporadic: occasional, random cases E. Epidemiology:the study of diseaseoccurrence, distribution,and transmission IV. Evolution of Disease Treatment A. Paul Ehrlich (1909):developedSalvarsan(first targeteddrug for syphilis) B. Sulfanilamide (1936):first widely usedantibiotic C. Penicillin (1928, Alexander Fleming):revolutionizedbacterial infection treatment D. Streptomycin (1944):FirstTB treatment, derived fromsoil bacteria V. Acute v. Chronic Diseases A. Acute Non-Infectious Diseases 1. Short-term, sudden onset(resolves in days or weeks) 2. Examples: a) Heart attack b) Stroke c) Hypoglycemia (low blood sugar) d) Cardiac arrest B. Chronic Non-Infectious Disease 1. Long-term, often lifelong 2. Examples: a) Diabetes b) Osteoporosis c) Cancer d) Hypertension e) Alzheimer’s f) Depression VI. Geriatric Pharmacology (Elderly & Medications) A. Elderly = 12% of the population but consume 31% of prescribed drugs B. Healthcare costs for 65+ are 3-5x higher than for younger individuals C. By 2030, healthcare spending will increase by 25% due to aging D. Challenges in Elderly Drug Use 1. More sensitive to drugsdue toaltered metabolism 2. Polypharmacy(taking multiple drugs) increasedruginteractions 3. 50% of all medication-related deaths occur in the elderly 4. 16% of hospital admissionsare due toadverse drugreactions VII. The Immune System & Disease A. Autoimmune Diseases 1. Body attacks itself 2. Examples: a) Multiple sclerosis:damagesnerve coverings b) Grave’s disease:affectsthyroidfunction c) Lupus:can affectmultiple organs or just skin d) Rheumatic fever: antibodies attack the heart B. Immunodeficiency 1. Severe Combined Immunodeficiency (SCID): a) “Bubble Boy” syndrome: no functional immune response b) Patients requireisolation or gene therapy VIII. Pharmacology: How Drugs Work A. Pharmacokinetics v. Pharmacodynamics: 1. Pharmacokinetics: what the body does to the drug(ADME) 2. Pharmacodynamics: what the drug does to the body(effectson target cells) B. Drug Targets & Therapeutic Outcomes 1. Most drugs act on proteins(enzymes, receptors) 2. Therapeutic Index (TI) = TD50/ED50: a) Low TI= high risk b) High TI= safer C. Key Terms 1. Prophylactic:prevents disease (ex. vaccines) 2. Palliative:relieves symptoms without curing (ex.painkillers) 3. Therapeutic: cures or treatsdisease 4. Tolerance:reduceddrug effect over time 5. Efficacy:howwella drug works 6. Potency: how muchdrug is needed to get an effect IX. Pharmacoeconomics (Cost of Healthcare & Drugs) A. 95% of healthcare costs for elderly = chronic diseases B. Cost-Effectiveness Studiesmeasure: 1. Cost per life-year saved(ex.$5,900 for beta-blockerspost-heart attack) 2. Q uality-Adjusted Life Years (QALYS): balancing cost v. heath improvement X. Modern Drug Advances A. GLP-1 Agonist (Diabetes & Weight Loss) 1. Originally for diabetes; not used for weight loss 2. Examples: Ozempic, Wegovy, Mounjaro 3. Side Effects: a) Possible intestinal blockage(FDA warning) b) 2022-2023 shortages due to high demand B. CAR-T Therapy (Cancer Immunotherapy) 1. Genetically engineered T-cellsattack cancer cells 2. Approved in 2017for leukemia & lymphoma 3. Extremely expensive: a) Kymriah (leukemia): $475,000 per treatment b) Yescarta (lymphoma): $373,000 per treatment 4. FDA Investigation: some CAR-T patients developedsecondary cancers XI. Final Takeaways A. Infectious diseases spread, while non-infectious diseases arise from genetics, lifestyle, or environment B. Epidemiology helps track disease patterns C. Medical history shows progress from natural remedies to targeted drugs D. Geriatric patients face unique challenges with drug metabolism E. The immune system plays a crucial role in both protecting and harming the body F. Modern treatments like GLP-1 agonists and CAR-T therapy how the future of medicine Week 4: How and Why Drugs Work or Don’t Learning Objectives: - What makes a good drug? - Challenges in drug discovery - Reasons for drug failures - Examples of successful and failed drugs I. Drug Development Process A. Drug discovery is difficult and expensive B. Cost:$0.8 - $2.0 billion per drug C. Limited patent life:companies must recoup costs beforegenerics enter the market II. Routes of Drug Administration A. Oral (tablets, syrups): slow, safest, most common(~20 min onset) B. Intravenous (IV): fastest (~15 sec to brain), highrisk . Inhalation: quick, can be dangerous (ex. lung disease risk) C D. Other routes: sublingual, rectal, topical, transdermal,vaginal, parental (injections) III. What Makes a Good Drug? A. Target specificity:acts only where needed B. ADMET Properties 1. Absorption: must be well absorbed 2. Distribution:must reach the right tissues 3. Metabolism:needs proper breakdown 4. Exertion:should clear safely 5. Toxicity:minimal harmful effects C. Therapeutic Index (TI): 1. TI =TD50/ED50(Toxic Dose 50% / Effective Dose 50%) 2. Low TI: dangerous (ex. alcohol TI ~10, opioids) 3. High TI: safer (ex. remifentanil TI ~33,000) IV. Challenges in Drug Development A. Selecting the right dose:too low = ineffective, toohigh = toxic B. Phase III Trials:failures are costly and often preventable C. Common reasons for drug failures: 1. Inadequate basic science 2. Wrong dose selection 3. Misjudging disease landscape 4. Poor study design 5. Flawed data collection 6. Operational problems D. Phase III trial failures cost companies millions to billions of dollars V. Drug Safety and Toxicity A. Paracelsus’ Principle:“All substances are poisons;the right dose differentiates a poison and a remedy” B. Acetaminophen Toxicity: 1. >4g/daychronic use -> liver failure 2. 10-15g/dayacute dose -> severe hepatotoxicity 3. Alcohol use worsens toxicity(induces enzymes thatincrease toxic metabolites) VI. Geriatric Pharmacology A. Elderly =12% of population, 31% of drug consumption B. Challenges: 1. Altered drug metabolism (slower clearance) 2. Polypharmacy:dangerous interactions 3. 50% of all medication-related deathsoccur in elderly 4. 16% of hospital admissionsdue to adverse drug reactions VII. Pharmacogenetics: Why Do Drugs Work Differently for People? A. Genetic mutations affect drug metabolism: 1. C YP2D6 mutation:affects metabolism of beta-blockers, antidepressants, etc. 2. G6PD deficiency(400 million people): increases riskof hemolysis with some drugs B. Food-Drug Interactions 1. Grapefruit juice:inhibits CYP3A, affecting drug breakdown 2. Calcium-rich foods:reduce tetracycline absorption 3. High-fat meals:can enhance drug absorption VIII. Examples of Drug Failures A. Rofecoxib (Voxx) Controversy: 1. Approved in1999, withdrawn in2004 2. Caused~139,000 heart attacks, 40% fatal 3. Studyomitted 3 myocardial infarction cases B. Pfizer’s Cholesterol Drug Failure (2016): 1. Competing withRepathaandPraluent, but sales werepoor 2. PCSK9 inhibitors (cholesterol drugs)reduce LDL by60%but are expensive C. Sterility Concerns (2021): 1. Sagent Pharmaceuticals recalled seizure drugdue tosterility failure 2. No reported adverse reactions, but potential risk ofsepsis and death IX. Recent Drug Advances A. CAR-T Therapy (Cancer Immunotherapy) 1. T-cells are genetically engineered to fight cancer 2. FDA-approved in 2017, but expensive: a) Kymriah(for leukimia):$475,000 per treatment b) Yescarta(for lymphoma):$373,000 per treatment 3. New FDA investigation:Some CAR-T patients developingsecondary cancers X. GLP-1 Agonists and Weight Loss A. Originally for diabetes, now repurposed for weight loss B. Examples: 1. Ozempic, Wegovy, Mounjaro(injectables) 2. Rybelsus(oral version) C. Shortables emerged in 2022-2023 due to high demand D. Side effects:potentialintestinal blockage(FDA warningissued) XI. The Future of Obesity Drugs A. Obesity drugs may also help with: 1. Depression 2. Addiction 3. Schizophrenia 4. Alzheimer’s 5. Parkinson’s B. Novo NordiskandEli Lillyare working onnext-genobesity drugs XII. Final Takeaways . A good drug must be effective, safe, and reach the right target A B. Drug discovery is expensive ($1B+), time consuming, and prone to failure C. Drug safety requires balancing benefits v. risks (therapeutic index) D. Geriatric and genetic factors make drug responses highly individual E. Pharmacogenetics and new therapies (CAR-T, GLP-1) are changing the landscape Week 5: Guest Speakers Role of ADME in Drug Development (Kulkarni) I. Stages of Drug Development A. Drug Discovery Research:identifies potential drugcandidates B. Preclinical Studies:animal testing for safety & efficacy C. Investigational New Drug (IND) Filed:approval tobegin human trials D. Phase I Clinical Trials:safety & dosage in healthyvolunteers E. Phase II Clinical Trials:effectiveness & side effectsin patients F. Phase III Clinical Trials:large-scale testing forsafety & efficacy G. New Drug Application (NDA) Filed:FDA reviews forapproval H. Market Approval & Post-Market Surveillance II. Why is ADME Important? A. Only ~1 out of 10,000 compounds reaches the market B. Most drug failures are due to: 1. Lack of bioavailability 2. Toxicity 3. Insufficient efficacy C. ADME studies help identify “drop-outs” early to save time & costs D. Understanding ADME helps predict: 1. Adverse effects 2. Therapeutic index (safety margin) 3. Dose-response relationships III. Pharmacokinetics: Drug Movement Through the Body A. A molecule should: 1. Have anoptimal half-life(not too short or too long) 2. Avoidexcessive first-pass metabolism(breakdown beforereaching the bloodstream) 3. Have good absorption & bioavailability (reach target site effectively) B. Formulations can improve bioavailability(ex. lipid-basedformulations for poorly soluble drugs) C. Key PK Parameters Parameters Definition Tmax Time to reach maximum concentration (Cmax) in plasma Cmax Maximum plasma drug concentration Half-life (T1/2) ime for drug concentration to decrease by T 50% AUC (Area Under Curve) Total drug exposure over time Clearance (CL) How quickly the body eliminates the drug Bioavailability (F%) of drug that reaches the bloodstream % unchanged D. Bioavailability formula:𝐹% = ( ) ( 𝐴𝑈𝐶𝑃𝑂 𝐴𝑈𝐶𝐼𝑉 × 𝐷𝑜𝑠𝑒𝑃𝑂 𝐷𝑜𝑠𝑒𝐼𝑉 ) × 100 . Most companies aim for F% ≥ 20% E IV. Drug Metabolism & First-Pass Effect A. Metabolism is key in drug discovery! B. Questions to consider: 1. Is metabolism different across species? 2. Are the metabolites toxic? 3. Does the drug induce or inhibit CYP450 enzymes? C. First-Pass Metabolism (Liver) 1. Oral drugs pass through the liver before reaching circulation 2. High first-pass metabolism = low bioavailability 3. Solutions: a) Prodrugs(inactive form activated in the body) b) Alternative routes (ex. IV, transdermal) V. Barriers to Drug Exposure A. Physiological barriers limit drug absorption & distribution 1. Examples: cell membranes, enzymes, pH differences,transporters B. Ideal drug properties: 1. Goodabsorption & distribution 2. Lowmetabolism & excretion (unless needed for clearance) 3. Lowtoxicity C. Permeability & Transporters 1. Permeability: rate at which a drug crosses biologicalmembranes 2. Improved by: a) Reducingionizable groups b) Increasinglipophilicity (LogP) c) Decreasingmolecular size & polarity 3. Membrane Transporters: a) P-glycoprotein (P-gp) Efflux: (1) Removes drugs from cells, reducing bioavailability (2) Found inBBB, intestines, kidneys, cancer cells VI. Blood-Brain Barrier (BBB) & Drug Distribution A. BBB prevents many drugs from entering the brain B. Brain penetration strategies: 1. Reducehydrogen bonding & molecular weight 2. Increaselipophilicity (LogP) 3. AvoidP-gp efflux & plasma protein binding C. Volume of Distribution (Vd) 1. Vd measures how widely a drug is distributed in the body 2. Not an actual volume, but an indicator of distribution Drug Type Vd Value Characteristics Hydrophilic (stays in blood) ~0.07 L/kg Confined to plasma Moderate Distribution ~0.7 L/kg Evenly distributed Lipophilic (Stored in Tissues) ~1 L/kg Binds fat & tissues VII. Clearance (CL) & Half-Life (T1/2) A. Clearance (CL):how quickly the drug is removed fromcirculation 1. Main organs: liver & kidneys B. Half-Life (T1/2): 0.693× 𝑉 𝑑 1. Formula:𝑇1/2 = 𝐶𝐿 . Short T1/2-> frequent dosing needed 2 3. LongT1/2-> less frequent dosing, but risk of accumulation VIII. Drug-Drug Interactions (DDIs) A. CYP450 enzyme inhibition & inductioncan alter drugmetabolism B. Time-dependent interactions & transporter-mediated effectsmust be considered C. Plasma Protein Binding 1. Drugs bind to albumin, ɑ-acid glycoprotein, or lipoproteins 2. Only free (unbound) drugs can act on targets & be eliminated 3. High protein binding -> less free drug available IX. Metabolic Stability & Drug Design A. Metabolism affects oral bioavailability, clearance, and half-life B. Occurs mostly in the liver (some in intestines) C. Metabolism optimization strategies: 1. ReduceCYP450 metabolismto increase drug stability 2. Modifyfunction groupsto reduce reactive metabolites 3. Increasehydrophilicityfor better excretion X. Therapeutic Window & Toxicity A. Therapeutic window:balance betweenefficacy & toxicity B. Key challenges: 1. Off-target effects . Reactive metabolites (toxicity) 2 3. Cardiotoxicity (hERG channel inhibition) XI. Large Molecules (Biologics) A. Peptides, proteins, and antibodieshave unique ADMEchallenges B. Usually administered IV or SC(poor oral bioavailability) C. Complex metabolism & elimination pathways Innovation in the Global Drug Discovery Ecosystem (Pacifici) I. Where Does Drug Discovery Start? A. Drug discovery begins with choosing the project & target B. Key Considerations: 1. Human genome (~35,000 genes) v. chemical diversity (10200) 2. Prioritization of biologically relevant targets 3. Balancing chemical & biological tractability II. Who Drives Drug Discovery? A. Pharmaceutical Companies 1. Market-driven (focus on blockbuster drugs) 2. Strong development & sales networks 3. Short attention span, often outsource innovation B. Disease Foundations 1. Focus on rare/neglected diseases (~7,000+ worldwide) 2. Long-term commitment, transgenerational funding 3. Major new players in drug development (>$1 billion impact) C. Academic Researchers 1. Driven by scientific discovery & publications 2. Huge source of innovation but often lacks funding for clinical trials 3. Challenges: “lone-ranger” syndrome, reproducibilityissues D. Biotech Companies 1. Focused innovation & technology-driven drug development 2. Often partner with pharma for late-stage trials 3. Limited disease expertise, volatile industry E. Aging Population & Consumer Demand 1. Unrealistic expectations (100% safe, free, instant cures) 2. Strong influence via activism & Participation III. Key Risks in Drug Discovery A. Biology-Driven Risks 1. Never identifying a viable target 2. On-mechanism toxicity (drug interacts with intended target but causes harm 3. Weak disease association or poor model validation B. Chemistry-Driven Risks 1. Compounds failing due to solubility, potency, selectivity, or stability 2. Formulation & intellectual property (IP) hurdles . ADME challenges (poor pharmacokinetics, rapid metabolism) 3 C. Clinical Trial Risks 1. Poor trial design, incorrect patient population selection 2. Statistical issues (low power, incorrect endpoints) 3. Unexpected toxicity in animals or humans IV. The Drug Discovery Pipeline A. Target Identification & Validation B. Hit Identification (screening for active compounds) C. Lead optimization (improving chemical properties) D. Candidate Selection (best compound for clinical trials) E. Preclinical Testing (animal studies & toxicity assessments) F. Clinical Trials (Phase I-III, human testing for safety & efficacy) V. CHDI: A Non-Profit Drug Discovery Model A. Mission: exclusively dedicated toHuntington’s Disease(HD) B. Approach: 1. No competitors, only collaborators 2. Fully integrateddiscovery-to-clinicalresearch 3. 90+ internal staff, 700+ external contract researchers 4. No internal labs:all work outsourced to leading institutions 5. Privately funded (~$100M per year) C. Key Benefits of Non-Profit Model: 1. Focus onone disease(no market pressure for quickreturns) 2. Preclinical rigor(avoids hype & ensures quality research) 3. Industry partnershipswithout financial conflicts VI. Huntington’s Disease (HD): Key Insights A. Genetic Disorder: 1. Autosomal dominant inheritance (100% penetrance) 2. Mutation in HTT gene (CAG repeat expansion) B. Symptoms: 1. Progressiveneurological degeneration(striatum &basal ganglia) 2. Late-onset (~40 years old), fatal within 10-15 years C. No cure:current treatments only manage symptoms D. “Huntington’s patients provide the keys” 1. Larger CAG repeat expansions = earlier onset 2. Modifier genes influence disease progression VII. Challenges in Animal Models for Huntington’s Disease A. Mouse Models (“HD Mice”) 1. Express single transgene, but can’t fully replicate40 years of human diseasein weeks 2. $30M spent testing 30+ compounds -> 0 successful candidates 3. Models must befit for purpose(predict human outcomeseffectively) Week 6: Defining a Market for Your Drug Learning Objectives: - The importance of understanding your market - The importance of product planning - Important market parameters - The importance of the target product profile I. Why is Understanding the Market Important? A. Market researchhelps determine the potential successof a drug B. Product planningensures that development aligns withmarket needs C. Target Product Profile (TPP)sets expectations forapproval and commercialization II. Key Market Considerations for Drug Development A. Should this product be pursued? B. What priority should it have within the company’s portfolio? C. What resources (financial, personnel) should be allocated? D. When should the project be discontinued if it’s not viable? E. Market size, competition, and differentiation are critical in decision-making III. Factors That Impact Drug Success A. Market Size & Distribution 1. Large market:more competition but high revenue potential 2. Niche market:less competition but small patient population B. Drug Positioning 1. First-in-Class:the first drug with a new mechanismof action 2. Second-Mover:enters after the first, possibly withimprovements 3. Generic:a copy of a branded drug after the patentexpires C. Product Attributes 1. Efficacy & Safety:how well does it work comparedto alternatives? 2. Patent Opportunities:stronger patents extend marketexclusivity IV. Challenges in Drug Development A. High costs(often exceeds $2 billion per drug) B. Long development timelines(10-15 years from discoveryto approval) C. Low success rate(only1 in 10,000drugs reach themarket) D. Short exclusivity periodbefore generics enter themarket E. Need to Maximize Return on Investment (ROI) V. Who Will Develop Your Drug? A. Large Pharmaceutical Companies 1. Fully integrated (R&D, manufacturing, marketing) 2. Access tolarge-scale funding& global distribution 3. May prioritize blockbuster drugs over niche markets B. Mid-Size Pharma Companies 1. Haveinfrastructure & financial backing 2. Oftenpartner with larger companiesfor distribution C. Startups & Biotech . Innovative,nimble, research-driven 1 2. Limited cash flow, high-risk venture 3. Oftenrely on partnerships or acquisitions VI. Assessing Company Competency A. What does the company do well? B. What are its weaknesses? C. Where does it fit in the marketplace? D. What is its patent position? E. Who are potential collaborators & allies? F. Strategic partnerships can make or break a drug’s success VII. Finding Your Niche in the Market A. Unmet Medical Need:a drug that treats conditionswith no existing therapies B. First-in-Class:a novel treatment approach C. Best-in-Class:an improvement over existing drugs D. Orphan Drug:treats rare diseases (
