NEW DRUG
DEVELOPMEN
T
Moderator – Dr.Amitabh kumar , Professor
Presenter – Dr.Sriharsha Rayam
INTRODUCTION
• Average time to develop new drug is 10 -12 years.
• On an average out of 10,000 – 30,000 potential
substanc...
 unmet medical need;
 new diseases ( AIDS, Alzheimer’s; obesity);
 low efficacy (dementia, cancer);
 side effects (ant...
• Folk medicine - natural product remedies
• Early 19th century - extraction of compounds from plants
(morphine, cocaine )...
1909 - First rational drug design.
• Goal: safer syphilis treatment than Atoxyl.
• Paul Erhlich and Sacachiro Hata wanted ...
• Mid to late 20th century
- understand disease states, biological structures, processes,
drug transport, distribution, me...
Drug development process – 3 main phases
• 1.drug discovery phase
• 2.preclinical phase
• 3.clinical trial phase
Drug discovery phase
1. Random screening
2. Serendipity ( By chance )
3. Rational drug designing
4. Designing of a prodrug...
1.RANDOM SCREENING
• Blind hitting procedure where new chemical
entities are subjected to pharmacological
screening proced...
2.SERENDIPITY (BY CHANCE / HAPPY
OBSERVATION)
• New use from old drug or its side effects
• Lignocaine & Phenytoin
• Metho...
3.RATIONAL DRUG DESIGNING
• A. compound centered approach
: from natural products – Pencillin,paclitaxel,cyclosporine
DA –...
B. Target centered approach
* Biochemical or molecular targets
Ex: ACE blockers or AT II blockers
-Now a days large number...
4. DESIGNING OF A PRODRUG OR AN
ACTIVE METABOLITE AS A DRUG
• Administered as the precursor of a drug and is converted
int...
Drug sources
• After the synthesis or isolation of the compound =
• Purity by physico chemical and analytical studies
Then these are su...
Leads are optimised with respect to
Pharmacodynamic properties-efficacy, potency,
selectivity.
Pharmacokinetic propertie...
PRECLINICAL EVALUATION PHASE ( ANIMAL
STUDIES)
Major areas are:
 Pharmacodynamic studies In vivo in animals, In vitro
pre...
Pharmacodynamic studies
•Action relavent to proposed therapeutic use are
studied on animals
Ex: Antihypertensive activity ...
Pharmacokinetic profile
 New compounds subjected in several species of
animals.
 Studies should establish
a) Relative bi...
Acute toxicity
 Acute toxicity studies most commonly median lethal
dose
i.e. LD50 is determined.
 Drug is given in grade...
Sub acute toxicity
 To identify target organs susceptible to drug toxicity.
 Laboratory studies like hematology, renal ,...
Test for fertility & reproductive performance
 Carried out in rats, treated with new drug before & after
mating period.
...
Genotoxicity/ Mutagenicity:
It is invivo – invitro test conducted to detects
compounds which induces genetic damage direct...
CARCINOGENECITY :
• for all drugs that are expected to be clinically used
for six months as well as for drugs used frequen...
LOCAL TOXICITY:
These studies are required when the new drug is proposed
to be used by some special route in human.
 Derm...
3. Rectal tolerance test-
Animals: rabbit & dog
Parameters: sign of pain, blood/mucus in faeces,
histopathology of rectal ...
3.Therapeutic index
 Relative margin of safety of a drug
TI =LD50/ED50
• Maximum Tolerated Dose
• No Adverse Effect Dose
...
REDUCING ANIMAL
USAGE
• About 2.6m animals/y used in procedures in UK (11.6m in Europe)
• Likely to increase; more researc...
CLINICAL TRIAL PHASE(HUMAN PHASE)
• To determine safety & efficacy of a new drug in humans
• Good clinical practices (GCP)...
IND APPLICATION
• When the new compound passes the preclinical phase ,
manufacturer may file a Investigational New Drug (I...
 Eight basic elements of informed consent
 purpose of the research
 risks or discomforts
 any benefits to the subject ...
Ethics committee & its
responsibilities
• At the institutional level – independent E.C to ensure
rights & welfare of the p...
ROLE OF PLACEBO
• Placebo controls – on healthy volunteers – Appetite
stimulant or new vaccine
• No place – Pt suffering f...
PHASES OF CLINICAL TRIALS
• 4 phases
phase I
phase II
phase III
phase IV
PHASE 1 CLINICAL TRIALS :
• Begins after 30 days of filing IND.
• Drug given to 20-100 healthy volunteers
• Duration could...
 Phase I studies are carried out in 2 stages
Single rising dose
Repeat administration
 Each volunteer given a single d...
 Started after single dose administration results
assessed.
 Drug / placebo given repeatedly for 1 or more weeks
E. g. ...
PHASE 2 CLINICAL TRIALS :
• Therapeutic exploratory trial
• First time in patients
• Less than 300 patients
• Doses are us...
1. Efficacy in patients
2. Safety issues
3. Optimum dose finding
 Dose efficacy relationship
 Therapeutic dose regimen
...
PHASE II DIVIDED INTO EARLY & LATE
PHASE
• EARLY PHASE II
small number of pts – upto 200
detail therapeutic benefited & AD...
PHASE 3 CLINICAL TRIALS :
• By several physicians at many centres
• Large scale – 1000 to 5000 plus
• To further establish...
Pts groups Week 1 Week 2 Week 3
I
STANDARD
DRUG
PLACEBO NEW DRUG
II
PLACEBO NEW DRUG STANDARD
DRUG
III
NEW DRUG STANDARD
D...
NDA
• NDA Refers to New Drug Application
• Formal proposal for the FDA to approve a new drug for
sale
• Sufficient evidenc...
PHASE IV
• launched to the Market
• Post marketing surveillance – field trails
• No fixed duration
• To discover relativel...
PERIODIC SAFETY UPDATE REPORT
(PSUR)
• Report any new information about the new drug & its
safety
• Every 6 months for 2 y...
EXAMPLE: THALIDOMIDE
Thalidomide was developed by German pharmaceutical company
Grünenthal. It was sold from 1957 to 1961 ...
Birth defects
caused by use of thalidomide
EXAMPLE: THALIDOMIDE
From 1956 to 1962, approximately 10,000 children were born
with severe malformities, including phocom...
Pharmacovigilance
• Pharmakon – a drug , vigilare – to be observant
• Continuous monitoring for unwanted effects & other
s...
• INDIA ,National P.V centre – AIIMS, New Delhi by central
drug standard control organization (CDSCO)
• 2 zonal , 8 region...
• Pharmaceutical companies are commercial enterprises
• Pharmaceutical companies will, therefore, tend to avoid
products w...
Most research is carried out on
diseases which afflict “first world”
countries: (e.g. cancer,
cardiovascular diseases,
dep...
The Orphan Drug Act
• The Orphan Drug Act of 1983 was passed to encourage
pharmaceutical companies to develop drugs to tre...
New tools for drug screening
HIGH THROUGHPUT SCREENING
Screening large libraries of 2 lakh compounds
Rate of 1,00,000 comp...
 Drugs are tested for their activity on these molecules using
plates wherein a large number of compounds are
simultaneous...
 Advantages
 Lead compound.
 Molecular mechanism.
 Minimizing cost and maximizing patent life time.
 Highly efficient...
 HTS is a remarkable achievement in drug discovery process
to speed up preclinical discovery process. This automation in
...
CASSETTE DOSING / N-IN-ONE DOSING
• Elegant, inexpensive , time intensive novel technique –
aim to rapidly assess P.K of l...
Micro dosing / First In Human( FIH) studies /
Phase O
•Study of new drug in microdoses to derive PK information in
human b...
• Microdosing approach in man could ‘accelerate’ drug
development without compromising clinical safety
• Microdosing helps...
Limitations
? Predictive accuracy of microdosing
PK at microdose vs. therapeutic dose
 False positive/ negatives
 Comp...
• 3rd world diseases?
• orphan drugs with few users?
• improve safety and efficacy records
• reduce animal utilisation (ce...
References :
• Pharmacological basis of Therapeutics – Goodman &
Gilman 12th Edition .
• Principles of pharmacology – HL S...
Thank u
new drug development by harsha
new drug development by harsha
new drug development by harsha
new drug development by harsha
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  1. 1. NEW DRUG DEVELOPMEN T Moderator – Dr.Amitabh kumar , Professor Presenter – Dr.Sriharsha Rayam
  2. 2. INTRODUCTION • Average time to develop new drug is 10 -12 years. • On an average out of 10,000 – 30,000 potential substances only 1 could make it to the market. • As per 2006 estimates, the cost of bringing a new drug could vary from 500 million to 2,000 million USD.
  3. 3.  unmet medical need;  new diseases ( AIDS, Alzheimer’s; obesity);  low efficacy (dementia, cancer);  side effects (antidepressants, antipsychotics)  cost of therapy; (Interleukins)  costs to individual/country; (Alzheimer’s; spinal injury, depression)  sustain industrial activity ( pharmaceutical industry employs thousands and makes a massive contribution to overseas earnings); patent expiry WHY ARE NEW DRUGS NEEDED?
  4. 4. • Folk medicine - natural product remedies • Early 19th century - extraction of compounds from plants (morphine, cocaine ) History of Drug Discovery…. • James Lind – Citrus fruits – Scurvy – clinical trail
  5. 5. 1909 - First rational drug design. • Goal: safer syphilis treatment than Atoxyl. • Paul Erhlich and Sacachiro Hata wanted to maximize toxicity to pathogen and minimize toxicity to human (therapeutic index). • They found Salvarsan (which was replaced by penicillin in the 1940’s)
  6. 6. • Mid to late 20th century - understand disease states, biological structures, processes, drug transport, distribution, metabolism. Medicinal chemists use this knowledge to modify chemical structure to influence a drug’s activity, stability, etc. • procaine = local anaesthetic; Procainamide = antirhythmic
  7. 7. Drug development process – 3 main phases • 1.drug discovery phase • 2.preclinical phase • 3.clinical trial phase
  8. 8. Drug discovery phase 1. Random screening 2. Serendipity ( By chance ) 3. Rational drug designing 4. Designing of a prodrug or an active metabolite as a drug
  9. 9. 1.RANDOM SCREENING • Blind hitting procedure where new chemical entities are subjected to pharmacological screening procedures • Studies on animal models , isolated tissues etc • It is time consuming, expensive, inefficient in providing fruitful results ,burdensome • Ex: • Morphine, Atropine , digitalis, Quinidine, cyclosporine
  10. 10. 2.SERENDIPITY (BY CHANCE / HAPPY OBSERVATION) • New use from old drug or its side effects • Lignocaine & Phenytoin • Methotrexate – psoriasis • Cyclophosphamide & Azathioprine – Graft rejection • Penicillin 1928, Fleming studied Staph, but contamination of plates with airborne mold. Noticed bacteria were lysed in the area of mold. A mold product inhibited the growth of bacteria: the antibiotic penicillin
  11. 11. 3.RATIONAL DRUG DESIGNING • A. compound centered approach : from natural products – Pencillin,paclitaxel,cyclosporine DA – complex molecules – difficult to synthesized : from synthetic products – from pharmacological data Ex: Based on proponolol structure- B blokers H2 blockers - modifying structure of histamine • Molecular modification ended up in molecular manipulation New drugs are serving as me too drugs , no added advantage
  12. 12. B. Target centered approach * Biochemical or molecular targets Ex: ACE blockers or AT II blockers -Now a days large number of drugs this way -Promising agents for lead optimisation
  13. 13. 4. DESIGNING OF A PRODRUG OR AN ACTIVE METABOLITE AS A DRUG • Administered as the precursor of a drug and is converted into active therapeutic agent Ex; Levodopa • Paracetamol, an active metabolite of phenacetin • N-acetyl procainamide, an active metabolite of procainamide does not cause SLE
  14. 14. Drug sources
  15. 15. • After the synthesis or isolation of the compound = • Purity by physico chemical and analytical studies Then these are subjected to biological screening LEAD COMPOUND - which have a potential of becoming new drug •compounds can elicit a positive response in a particular assay, which is called a hit. • “Lead” is a hit series for which the structure–activity relationship is shown and activity demonstrated both in vitro and in vivo
  16. 16. Leads are optimised with respect to Pharmacodynamic properties-efficacy, potency, selectivity. Pharmacokinetic properties- metabolic stability and toxological aspects Physiochemical properties Chemical optimisation-ease of chemical synthesis & derivation
  17. 17. PRECLINICAL EVALUATION PHASE ( ANIMAL STUDIES) Major areas are:  Pharmacodynamic studies In vivo in animals, In vitro preparation  Absorption, distribution , elimination studies (pharmacokinetics)  Acute ,sub acute, chronic toxicity studies (toxicity profile)  Therapeutic index (safety & efficacy evaluation)
  18. 18. Pharmacodynamic studies •Action relavent to proposed therapeutic use are studied on animals Ex: Antihypertensive activity – dogs,cats,rats To find out – B.P - ECG changes - inotropic & chrinotropic efforts - CO & t.p.r •Once L.C exibits promising results – futhur studies at cellular level •Receptor activity in vitro on cultured cells •Further extended to molecular level to find out receptor affinity & selectivity by performing in vitro studies on cell membrane fractions from organs •Graded response assy or Quantal assay - ED 50 of the drug
  19. 19. Pharmacokinetic profile  New compounds subjected in several species of animals.  Studies should establish a) Relative bioavailability of the compound on oral or parenteral administration b) Elimination half life for assessment of optimal dosage interval
  20. 20. Acute toxicity  Acute toxicity studies most commonly median lethal dose i.e. LD50 is determined.  Drug is given in graded doses to at least 2 animal species by at least 2 routes.  To minimize biological variation, animal groups should be similar.  Percentage of animals dying in each group within specified time (24 hrs) is plotted against the dose.  Other toxic symptoms suffered also recorded. Toxicity profile
  21. 21. Sub acute toxicity  To identify target organs susceptible to drug toxicity.  Laboratory studies like hematology, renal ,hepatic function test are carried out.  Animals are maintained at max. tolerated dose for 4 wks – 3 months & killed for HPE. Chronic toxicity  If drug intended for chronic use in humans.  2 species of animals ,1 rodent and 1 non rodent are used. Drug administered for many months (6-24 months),detailed biochemical & histological measurements are made.  To evaluate cumulative toxicity  To assist carcinogenic potential  Study may run simultaneously with clinical trial.
  22. 22. Test for fertility & reproductive performance  Carried out in rats, treated with new drug before & after mating period.  Effects on early & late stages of embryonic & fetal development are studied . Teratogenicity  Carried out in 2 animal species to assess the effects of drug on organogenesis.  Drugs given after mating  Fetuses are carefully examined for abnormalities.
  23. 23. Genotoxicity/ Mutagenicity: It is invivo – invitro test conducted to detects compounds which induces genetic damage directly or indirectly. The following standard test is generally expected to be conducted : 1. A test for gene mutation in bacteria – AMES test 2. An invitro test with cytogenetic evaluation of chromosome damage with mammalian cells 3. In vivo test for chromosomal damage using rodent Hematopoietic cells. Parameters: Frequency of damage cells ,Total number, types and frequency of metaphase chromosomal aberration
  24. 24. CARCINOGENECITY : • for all drugs that are expected to be clinically used for six months as well as for drugs used frequently in an intermittent manner in the treatment of chronic or recurrent condition • Animals : rodent 2 animal species , same dose of chronic study, for 2 years. • Parameters : Autopsy and detailed Histopathology of organ and tissues
  25. 25. LOCAL TOXICITY: These studies are required when the new drug is proposed to be used by some special route in human.  Dermal toxicity  Vaginal toxicity  Rectal tolerance test  Ocular toxicity 1. Dermal toxicity: Animals: rabbit & rat Parameters: erythema & edema 2. Vaginal toxicity: Animals: rabit & dog Parameters: swelling, closure of introitus & histopathology of vaginal wall.
  26. 26. 3. Rectal tolerance test- Animals: rabbit & dog Parameters: sign of pain, blood/mucus in faeces, histopathology of rectal mucosa. 4. Ocular toxicity- Animals: rabbit Parameters: Slit Lamp Test & Fluroscent Dye Test
  27. 27. 3.Therapeutic index  Relative margin of safety of a drug TI =LD50/ED50 • Maximum Tolerated Dose • No Adverse Effect Dose • Human Equivalent Dose
  28. 28. REDUCING ANIMAL USAGE • About 2.6m animals/y used in procedures in UK (11.6m in Europe) • Likely to increase; more research, more targets, genetic capability • 3Rs -- 3Rs -- 3Rs • REPLACEMENT: use non-animal tests if possible (cheaper, less trouble, less variable but not possible for everything at this time) • REDUCTION: get the statistics right, don’t replicate work unnecessarily, don’t overbreed • REFINEMENT: reduce suffering and severity of procedure, pay attention to housing, stress, husbandry and rich environments, proper analgesia and pre- and post- operative care
  29. 29. CLINICAL TRIAL PHASE(HUMAN PHASE) • To determine safety & efficacy of a new drug in humans • Good clinical practices (GCP) by international Conference on Harmonization (ICH) and declaration of Helsinki. • It provides details about – designing the trail - collection of data - recording of information - statistical analysis - documentation & reporting
  30. 30. IND APPLICATION • When the new compound passes the preclinical phase , manufacturer may file a Investigational New Drug (IND) application to authorized drug control body • In INDIA - drugs controller general,Govt.of india,Delhi • It contains information about the test drug – - source,structure,manufacturing data - preclinical data - dosage forms,investigational protocol - details about investigators - agreement from the sponsers - certification that Informed Consent will be obtained from volunteers
  31. 31.  Eight basic elements of informed consent  purpose of the research  risks or discomforts  any benefits to the subject which may reasonable be expected from the research  Any alternative procedures or treatment that may be available to the subject  confidentiality of records identifying the subject will be maintained  any compensation and whether any medical treatments are available if injury occurs  An explanation of whom to contact for answers to questions about the research and research subjects’ rights  A statement that participation is voluntary Informed consent
  32. 32. Ethics committee & its responsibilities • At the institutional level – independent E.C to ensure rights & welfare of the participants • Responsibilities - review protocol - safeguard the rights , safety of trail subjects - periodical review – SOPs • 7 members – Member secretary - chair person (outside) - medical & non medical persons
  33. 33. ROLE OF PLACEBO • Placebo controls – on healthy volunteers – Appetite stimulant or new vaccine • No place – Pt suffering from a disease – effective drug already available • Ethics – consent is taken
  34. 34. PHASES OF CLINICAL TRIALS • 4 phases phase I phase II phase III phase IV
  35. 35. PHASE 1 CLINICAL TRIALS : • Begins after 30 days of filing IND. • Drug given to 20-100 healthy volunteers • Duration could vary from 1 month to 1 year. • Following is studied here : • Drug absorption/Metabolism in human. • Effect on organs and tissues. -Side affect of different dosages. • Thus early evidences on effectiveness are achieved *NON BLIND OR OPEN LABEL TRAIL
  36. 36.  Phase I studies are carried out in 2 stages Single rising dose Repeat administration  Each volunteer given a single dose of drug/placebo.  Dose-escalating study design.  Initial dose and route of administration decided from existing pre-clinical data.  8 -12 volunteers .  2-4 volunteers receive placebo and 6-8 volunteers receive drug under study. STAGE 1–SINGLE RISING DOSE
  37. 37.  Started after single dose administration results assessed.  Drug / placebo given repeatedly for 1 or more weeks E. g. Antibiotics given for 5-7 days Anticonvulsants tested for 4 weeks or more  Interval between doses is usually one half life.  Kinetic data obtained from blood and urine sample collected after 1st and last dose STAGE 2 REPEATED ADMINISTRATION
  38. 38. PHASE 2 CLINICAL TRIALS : • Therapeutic exploratory trial • First time in patients • Less than 300 patients • Doses are usually less than the highest doses used in phase I *SINGLE BLIND TRAIL
  39. 39. 1. Efficacy in patients 2. Safety issues 3. Optimum dose finding  Dose efficacy relationship  Therapeutic dose regimen  Duration of therapy  Frequency of administration  Therapeutic window OBJECTIVES
  40. 40. PHASE II DIVIDED INTO EARLY & LATE PHASE • EARLY PHASE II small number of pts – upto 200 detail therapeutic benefited & ADR idea to establish dose range SINGLE BLIND STUDY • LATE PHASE II large number of pts – 200-400 DOUBLE BLIND STUDY third party holds the code identifying studies
  41. 41. PHASE 3 CLINICAL TRIALS : • By several physicians at many centres • Large scale – 1000 to 5000 plus • To further establish the safety & efficacy • Long term side effects in patients • Duration could vary from 5 years to 6 years. • DOUBLE BLIND CROSS OVER design • At end of trail statistical analysis of data is performed
  42. 42. Pts groups Week 1 Week 2 Week 3 I STANDARD DRUG PLACEBO NEW DRUG II PLACEBO NEW DRUG STANDARD DRUG III NEW DRUG STANDARD DUG PLACEBO Double-Blind Cross Over design
  43. 43. NDA • NDA Refers to New Drug Application • Formal proposal for the FDA to approve a new drug for sale • Sufficient evidences provided to FDA to establish: • Drug is safe and effective. • Benefits outweigh the risks. • Proposed labeling is appropriate.
  44. 44. PHASE IV • launched to the Market • Post marketing surveillance – field trails • No fixed duration • To discover relatively rare side effects(congenital effects) or drug interactions • From hundreds to thousands of people • Usually takes place after drug is approved to provide additional information on the drug’s risks, benefits and optimal use
  45. 45. PERIODIC SAFETY UPDATE REPORT (PSUR) • Report any new information about the new drug & its safety • Every 6 months for 2 yrs & annually next 2 yrs Where the drug fails ?
  46. 46. EXAMPLE: THALIDOMIDE Thalidomide was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.
  47. 47. Birth defects caused by use of thalidomide
  48. 48. EXAMPLE: THALIDOMIDE From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy. In 1962, in reaction to the tragedy, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S. Phocomelia presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet.
  49. 49. Pharmacovigilance • Pharmakon – a drug , vigilare – to be observant • Continuous monitoring for unwanted effects & other safety related aspects of marketed drugs • Thalidomide, Isotretinoin , • Fenfluramine & Phentermine – PHTN & valvular H.D • Troglitazone – liver toxicity • WHO – safety monitoring of medical products - setting a P.V centre in every country • P.V – Detection,Assessment, Understanding and Prevention (DAUP) of ADR
  50. 50. • INDIA ,National P.V centre – AIIMS, New Delhi by central drug standard control organization (CDSCO) • 2 zonal , 8 regional & 28 peripheral P.V centres • Generated data – global P.V database at WHO-Uppsala monitoring centre-Sweden • Reporting ADR includes: -drug interaction -death -life-threatening reaction -hospitalization -disability -congenital abnormality
  51. 51. • Pharmaceutical companies are commercial enterprises • Pharmaceutical companies will, therefore, tend to avoid products with a small market (i.e. a disease which only affects a small subset of the population) • Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries) Choosing a Disease
  52. 52. Most research is carried out on diseases which afflict “first world” countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine, obesity). Choosing a Disease
  53. 53. The Orphan Drug Act • The Orphan Drug Act of 1983 was passed to encourage pharmaceutical companies to develop drugs to treat diseases which affect fewer than 200,000 people • Because the cost incurred will not be recovered • So rare diseases are left untreated – orphan diseases , drugs – orphan drugs • Govt. offered tax relief and exclusive marketing rights • > 300 drugs Ex: factor XIII , Erythropoietin , Atravaquone , Antithrombin III , Miltefosine , Acetyl cysteine , Relaxin
  54. 54. New tools for drug screening HIGH THROUGHPUT SCREENING Screening large libraries of 2 lakh compounds Rate of 1,00,000 compounds/day In HTS chemicals are tested for their ability to modify a target Methods – screening of combinatorial chemistry ,genomics, proteomics & peptide libraries
  55. 55.  Drugs are tested for their activity on these molecules using plates wherein a large number of compounds are simultaneously tested.  Screening depends on inhibition of enzymic products which are detected using fluoroscopy or photometry  Instrumentation  24 WELL PLATE.  96 WELL PLATE. - COMPOUND STORAGE. - COMBINATORIAL CHEMISTRY. - SAMPLE COLLECTION. -SCREENING.  384 WELL PLATES. -LOW VOLUME -DNA LIBRARY MANIPULATION.  1536 WELL PLATES.
  56. 56.  Advantages  Lead compound.  Molecular mechanism.  Minimizing cost and maximizing patent life time.  Highly efficient development.  Disadvantages  Availability Of Instruments.  Trained Personnels.
  57. 57.  HTS is a remarkable achievement in drug discovery process to speed up preclinical discovery process. This automation in the process is supported by the excellent software packages. .  The goal of the HTS is to accelerate drug discovery by screening large libraries at a rate that may exceed 50,000 compounds per week.
  58. 58. CASSETTE DOSING / N-IN-ONE DOSING • Elegant, inexpensive , time intensive novel technique – aim to rapidly assess P.K of large number of compounds • Several compounds(5-10) to single animal & rapid sample analysis by liquid chromatography or mass spectography • Advantages – to reduce no. of animals - increased quality of kinetics data - reduce the amount of the drug - time minimized • Disadvantages – drug to drug interactions - false positives
  59. 59. Micro dosing / First In Human( FIH) studies / Phase O •Study of new drug in microdoses to derive PK information in human before undertaking phase I studies is called PHASE 0 •“1/100th or lower of the expected therapeutic dose.” A dose less than 100ug •(The test compound has no pharmacologic effect at microdose concentrations)
  60. 60. • Microdosing approach in man could ‘accelerate’ drug development without compromising clinical safety • Microdosing helps researchers select better drug candidates for clinical trials by providing early human PK and bioavailability data. • Reduced cost of development • Reduced development time Objectives Primary: Determine the pharmacokinetics Determine a non -toxic dose range Secondary : Determine the safety of an chemical entity
  61. 61. Limitations ? Predictive accuracy of microdosing PK at microdose vs. therapeutic dose  False positive/ negatives  Compound metabolism and solubility (limited solubility at higher doses; ? Microdose too small)  Study mainly based on PK parameters - not efficacy and safety based
  62. 62. • 3rd world diseases? • orphan drugs with few users? • improve safety and efficacy records • reduce animal utilisation (cell lines; early human volunteers, ) • new diseases (AIDS; Alzheimer’s; CJ disease;human BSE variant; obesity; cancer) • new biology - (clone human receptors; disease model by gene changes) The future ?
  63. 63. References : • Pharmacological basis of Therapeutics – Goodman & Gilman 12th Edition . • Principles of pharmacology – HL Sharma & KK sharma 2nd edition . • Drug Screening methods – Gupta 2 nd edition • Experimental Pharmacology – Bikash Medhi • Text book of pharmacology – K. D. Tripathi.7th Edition. • Basics & clinical pharmacology – Katzung 11th edition • www.history of clinicaltrails.in
  64. 64. Thank u
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