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Drug discovery and development


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A presentation outlining the various processes a chemical compound undergoes (thorough & rigorous screening procedures) before it is finally introduced into the drug market

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Drug discovery and development

  2. 2. INTRODUCTION Creation of a new drug involves :- 1. Drug discovery (Research) :- Identification of a potential therapeutic target  Selection of a single molecule for testing in humans. 2. Drug development (Development) :- Preclinical studies that support initial clinical trials through approval of the drug by regulatory authorities. 3. Commercialization (Marketing) :- Product  Therapeutic application  Sales
  3. 3. Drug discovery process Process by which pharmaceutical, biotechnology, academic & Govt. laboratories identify or screen compounds to find potentially active therap. agents
  4. 4. Multidisciplinary nature of drug discovery
  5. 5. Drug discovery process
  6. 6. Stages of drug discovery
  7. 7. Target identification • Target  Molecular recognition site to which drug binds • Target may be • Protein molecule • A receptor • Enzyme • Transport molecule • Ion channel • Tubulin • Immunophilin
  8. 8. Therapeutic drug targets
  9. 9. Strategies to find new drug targets 1. Conventional strategies a) Analysis of pathophysiology b) Analysis of MOA of existing drugs 2. New strategies a) Disease genes b) Disease-modifying genes
  10. 10. Disease genes • Abl-kinase  Molecular target for Imatinib • Secretase inhibitors  Anti-Alzheimer drugs • Most promising field  Cancer therapies • Identifying d/s gene  Valuable pointers to drug targets
  11. 11. Disease modifying genes • Most important category • Approaches used :- 1. Gene expression profiling 2. Gene knockout studies
  12. 12. Gene expression profiling Principle  Development of any disease phenotype involves changes in gene expression in cells & tissues involved Method  DNA microarray (‘gene chips’)
  13. 13. DNA microarray
  14. 14. Cluster analysis of gene expression experiment (Dendrogram)
  15. 15. Gene knockout screening • Generation of transgenic ‘gene knockout’ strains of mice • Examples 1. Inactiv. Of gene for ACE/ATR  ↓ B.P. 2. Elim. Of gene encoding GABAA  Irrit. In mice 3. Cathepsin K  Osteoporosis 4. Melanocortin receptors  Obesity • Flatworm & zebrafish  Speed up the process
  16. 16. Target validation • Experimental approach by which a “potential” drug target can be tested & given further credibility • Main approach • Pharmacological  mGluR for pain • Genetic • Antisense oligonuceotides • RNA interference • Transgenic animals
  17. 17. Phase D0  ‘Target identification’ (Research with intent of identifying a therapeutic target) Phase D1 + D2  ‘Lead identification’ (Initial screening to discover chemical template for lead optimization).Tests include HTS,LTS(in vitro & in vivo) Phase D3  ‘Lead optimization’ (Optimiz. & biol. Testing of compound).Outcome  Best in potency & selectivity, as well as ADME properties Phase D4  Completion of studies to allow 1st application in man
  18. 18. Antisense Oligonucleotides Stretches of RNA complementary to gene of interest ↓ Bind to cellular mRNA (Prevent its translation) ↓ Inhibits expression of specific genes ↓ Role of ‘specific genes’ in disease phenotype can be determined
  19. 19. RNA interference Short lengths of dsRNA (siRNAs) ↓ Activate RISC (RNA induced silencing complex) ↓ Destroys corresponding fmRNA in the cell ↓ Gene silenced
  20. 20. Transgenic animals
  21. 21. Important definitions • Screening  Testing many compounds in assays relevant to the disease in question • Hit  A compound that passes such a ‘screen’ • Primary hit  Compound giving positive result in a screening assay • Confirmed hit  Compound is confirmed as positive when assay is repeated • Validated hit  Confirmed hit that shows selective activity
  22. 22. • Lead compound  A new chemical entity that could be developed in a new drug by optimizing beneficial effects & minimizing S/E Should comply with Lipinski’s rule of 5 :- • Mol. Wt. < 500 Da cLogP < 5 • No. of H bond donors <5 Sum of no. of Ns & Os <10 • Drug candidate  End result of lead optimization (A compound judged suitable for precl. & cl. Develop.) • Development compound  Drug candidate that has been accepted for further development
  23. 23. Screening 1. Selectivity screening  In vitro tests (If compound is selective to merit further investigation) 2. Pharmacological profiling • In vitro profiling  Study on isolated tissues has been the mainstay • In vivo profiling  Imaging technologies used • MRI • USG • PET • X-ray densitometry tomography
  24. 24. Animal models of disease 1. Acute physiological & pharmacological models • Seizures induced by electrical stimulation of the brain  Epilepsy • Histamine induced bronchoconstriction  Asthma • Eddy’s hot plate test  Pain • Injection of LPS & cytokines  Septic shock • Elevated plus maze test  Anxiolysis
  25. 25. 2. Chronic physiological or pharmacological models • Use of Alloxan / Streptozotocin  Type I DM • Inducing brain ischemia  Stroke • Inducing coronary ischemia  IHD • “Kindling”  Epilepsy • Self-admin. of opiates/nicotine  Drug dependence
  26. 26. • Cholesterol fed rabbits  Hypercholesterolemia & atherosclerosis • Immunization with myelin basic protein  MS • Admin. Of MPTP  Parkinson’s disease • Transplant. Of malignant cells into immunodef. Animals  Progressive tumors (Cancer)
  27. 27. 3. Genetic models 1. SHR 2. Seizure-prone dogs 3. Rats insensitive to ADH 4. Obese mice 1. CF 2. DMD 3. Leptin gene (mutated in ob/ob mice) 5. Alzheimer’s disease (APP)
  28. 28. Validity criteria (Willner 1984) 1. Face validity  Accuracy with which model reproduces the phenomena char. human d/s 2. Construct validity  Extent to which etiology of human disease is reflected in model 3. Predictive validity  Extent to which manipulation (drug t/t) is predictive of effects in the human disorder
  29. 29. Identification of hits 1. Compound centered approach  Traditional Compound is identified ↓ Biological profile is explored ↓ If compd. displays desirable pharmacologic activity ↓ Compound is refined & developed further
  30. 30. 2. Target centered approach Putative drug target (receptor/enzyme) is identified ↓ Researchers search for compounds which interact with target (agonist/antagonist/modulator) Search maybe: 1. Systematic  Uses info. About structure of target as a starting point 2. Shotgun approach  All compounds in a large library of substances are tested in a high-speed automated assay
  31. 31. High-throughput screening • Simplest target centered approach • Uses a target based assay & robotic automation to test thousands of compounds in a few days time • 2 critical aspects :- 1. A large library of compounds must be available for screening 2. Assay (Simple/sophisticated) that leads to rapid identification of true hits must be developed
  32. 32. Lead identification Library is “run through” the assay (96/384-well plate) ↓ ‘Primary hits’ are examined more closely ↓ Further screening is done (To eliminate false positives & false negatives) ↓ Leads are advanced in ‘lead optimization’ process
  33. 33. Lead optimization Physical, chemical, biological & pharmacological properties of promising lead molecules (that appear to interact with the target in a desirable way) are Characterized & refined with the ultimate goal Of selecting a single molecule to enter into Clinical testing & formal drug development
  34. 34. Factors causing termination 1. Failure to demonstrate efficacy in a rigorous animal model of human disease 2. Low bioavailability 3. Extensive/complex metabolism  Potentially dangerous reactive metabolites 4. Toxic effects in preliminary animal toxicology studies 5. In vitro evidence that molecule may damage DNA 6. Extremely difficult chemical synthesis
  35. 35. Drug development
  36. 36. • All activities involved in transforming a compound from drug candidate  Product approved for marketing by appropriate regulatory authorities • Falls in 3 main parts :- 1. Technical development  Ensuring quality of end- product 2. Investigative studies  Safety & efficacy 3. Managerial functions  Co-ordination, documentation & liaison with regulatory authorities
  37. 37. Stages of drug development Stage No. of yrs. Synthesis/isolation of compound 1-2 Preclinical studies (Scr.,eval.,pk. & short term toxicity test. in animals) 2-4 Scrutiny & grant of permission for clinical trials 0.25-0.5 Pharmaceutical formulation, standardization of chemical/biological/immuno-assay of the compound 0.5-1 Clinical studies: Phase I,II,III trials; Long term animal toxicity testing 3-10 Review & grant of marketing permission 0.5-2 Post-marketing surveillance No fixed duration
  38. 38. Phases of Precl. & Clinical Development Phase Primary goal Dose Patient monitor Number of participants Preclinic al Testing of drug in non- human subjects Unrestricted A graduate level researcher-Ph.D. In vitro & in vivo animal models Phase 0 Oral bioavailability & half- life of drug Subtherapeutic Clinical researcher 10 people Phase I Testing of drug on healthy volunteers (safety) Subtherapeutic with asc. Doses Clinical researcher 20-100 people Phase II Testing of drug on patients (efficacy & tolerability) Therapeutic dose Clinical researcher 100-300 people Phase III Testing of drug on pts. (confirm efficacy) Therapeutic dose Clinical research. & Physician 1000-2000 people Phase IV Post-marketing surveillance (A/E, D-D I) Therapeutic dose Physician Anyone seeking treatment Phase V Translational research No dosing None All reported use DeMets D., Friedman L. and Furberg C.(2010).Fundamentals of Clinical Trials. Springer 4th Edition Goodman and Gilman's The Pharmacological Basis of Therapeutics, (2011) 12th Edition
  39. 39. Preclinical development Aim  Meet all requirements before a new compound is deemed ready to be tested for the 1st time in humans Work falls into :- 1. Safety pharmacology  Testing to check that drug does not produce hazardous acute effects 2. Preliminary toxicological testing  Eliminate genotoxicity & determine maximum non-toxic dose of drug (given daily for 28 days & tested in 2 species)
  40. 40. 1. Pharmacokinetic testing (ADME studies) in laboratory animals 2. Chemical & pharmaceutical dev 3. Pharmacokinetic testing (ADME studies) in laboratory animals 4. Chemical & pharmaceutical development  Assess feasibility of large scale synthesis & purification 5. Assess stability of compound under various conditions 6. Develop a formulation suitable for clinical studies • Work done in accordance with GLP
  41. 41. IND • New drug ready to be studied in humans  a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA • It includes :- 1. Info. on the composition and source of the drug 2. Chemical and manufacturing information
  42. 42. • Includes :- 1. Info. on the composition and source of the drug 2. Chemical and manufacturing information 3. All data from animal studies 4. Proposed plans for clinical trials 5. Names and credentials of physicians who will conduct the clinical trials 6. A compilation of the key data relevant to study of the drug in humans that has been made available to investigators and their institutional review boards
  43. 43. Phase 0 (Microdosing study) • Developed by FDA & EMA as “cost-cutting” tools Very low doses (1/100th of estimated human dose or max. of 100 µg total dose of candidate drug) are administered to healthy volunteers ↓ Pharmacok worked out using AMS with radiolabelled drug/LC-MS to measure ultra low drug levels
  44. 44. • Subpharm. dose  No toxic / therapeutic eff. But yields human pharmacokinetic information • Elaborate animal studies & costly phase I human trials could be avoided for candidate drugs • Useful in more precise selection of doses for phase I study • They are promising & most regulatory authorities are willing to allow & consider them
  45. 45. Phase I • Studies carried out  Phase I clinics (All vital func. Are measured & emergency/resuscitative facilities avail.) • Clinical investigators  Clinical pharmacologists • Trial subjects  Healthy volunteers (25-100) • Objectives :- 1. Check for safety (Drug affects CV, hepatic or renal functions adversely) 2. Check for tolerability (Drug produces unpleasant symptoms like headache, nausea & vomiting)
  46. 46. 1. 3. 2. 3. 3. Determine whether humans & animals show significant pharmacokinetic differences 4. Determine a safe clinical dosage range in humans (Common rule  Begin with 1/5th or 1/10th of MTD in animals & calc. it for 70 kg body wt.) 5. Determine the pharmacokinetics of the drug in humans (Whether deficiency in drug effect is due to lack of absorption / faster elimination) 6. Detect any predictable toxicity
  47. 47. Pharmacokinetic parameters 1. Cmax  Peak drug &/or metabolite concentration 2. Tmax  Time to peak drug &/or metabolite conc. 3. AUC0-∞  Area under conc.-time curve e.p. to inf. 4. AUC0-T  AUC calc. to a specific time point T 5. T1/2  Time taken for level of drug to dec. by 1/2 6. VD  Volume of distr. 7. CL  Clearance 8. MRT  Mean residence time (Avg. time a drug molecule rem. In body after rapid i.m. injection)
  48. 48. Dosing & blood sampling schedule for phase I studies
  49. 49. Phase II • Drug studied for 1st time in pts. with target disease • Main purpose  Gather evidence that drug has effects suggested by preclinical trials • End points :- 1. Definitive end point (Measures drug effect directly  Pain relief [analgesic]) 2. Surrogate end point (Predictive of the definitive end point  Reduction in tumor size[anticancer])
  50. 50. Phase IIa • “Proof of concept”/ “Proof of claims” • Preliminary evidence of efficacy & safety • Up to 200 pts. are studied  Potential therapeutic benefits & side effects are observed • Establishment of dose range for more definitive therapeutic trials in phase IIb • Study design  Single blind (Subject unaware if he is taking placebo/positive control/new drug)
  51. 51. Phase IIb • Dose-finding studies • To confirm efficacy with statistical significance • Determine the optimal dose & dosing regimen • Large no. of patients used (200-400) • Study design  Double blind (3rd party holds the code identifying each medication & this code is not deciphered until all clinical data has been coll.)
  52. 52. Phase III • Large scale, multicentered randomized double blind trials to further establish safety & efficacy • Made using “Double-blind cross over” designs to minimize errors • NDA  After completion of phase III trials, sponsors file a “New Drug Application” with the drug control authorities of that country • NDS  If documentation is acceptable & in compliance, drug enters market with NDS
  53. 53. Double blind Cross Over Design Pt. grp. (randomi zed) Week 1 Week 2 Week 3 I Standard drug Placebo New drug II Placebo New drug Standard drug III New drug Standard drug Placebo
  54. 54. Phase IV • Surveillance phase during the post marketing clinical use of the drug • Used to discover • Relatively rare side effects • Previously unknown drug interaction • Previously unknown therapeutic use detected by a chance discovery
  55. 55. Phase V • Aims to bridge the gap between basic and clinical research1 • Encompasses laboratory studies, clinical demands, public health and health management, policies and economics1 • Crucial in the evolution of contemporary biomedical science1 • It is used to signify the integration of a new clinical treatment into widespread public health practice2 1-Translational research: from benchside to bedside.N C Keramaris, N K Kanakaris, C Tzioupis, G Kontakis, P V Giannoudis Academic Department of Trauma and Orthopaedics, Leeds Teaching Hospitals, University of Leeds, Great George Street, Leeds LS1 3EX, UK.Injury (Impact Factor: 1.93). 07/2008; 39(6):643-50. DOI: 10.1016/j.injury.2008.01.051 Source: PubMed 2-Margaret A. Rogers (June 2009). "What are the phases of intervention research?". American Speech-Language-Hearing Association. Retrieved Jan 8, 2013.
  56. 56. Preclinical safety assessment 1. Exploratory toxicology • Rough estimate of toxicity (2 weeks) • Provides an indication of main organs & physiological systems involved 2. Regulatory toxicology (GLP) • Reqd. by regulatory authorities/EC before compound can be given for 1st time to humans • Studies reqd. to support an application for marketing approval
  57. 57. Timing of safety assessment
  58. 58. Genotoxicity • Mutagenicity  Chemical alteration of DNA sufficient to cause abnormal gene expression in the affected cell & its offspring • Chromosomal damage • End results  Carcinogenesis & Teratogenicity (detected by long-term animal studies)
  59. 59. Toxicokinetics “Generation of pharmacokinetic data, either as an integral component in the conduct of non-clinical toxicity studies, or in specially designed supportive studies, in order to assess systemic exposure” (ICH Guideline S3A) • Pharmacokinetics applied to toxicological studies
  60. 60. Toxicity measures 1. NTEL  Largest dose in most sensitive species 2. LD50  Estimated dose reqd. to kill 50% expt. An. 3. NOAEL  Largest dose causing neither tissue toxicity nor undesirable physiological effects 4. MTD  Largest dose tested causing no obvious signs of ill-health 5. NOEL  Threshold for producing any observed pharmacological or toxic effect
  61. 61. THANK YOU