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Making of an antibiotic Pre Clinical Journey Dr. Ashok Rattan Chief Executive, Fortis Clinical Research Ltd., Adviser, Rel...
We are overwhelmed as it is, with an infinite abundance of vaunted medicaments; and here they add a new one….. Thomas Syde...
Do we really need new  anti- infectives ? <ul><li>> 80 efficacious agents available to treat ALL bacterial ; most fungal i...
Yes, <ul><li>Drugs are required to meet  </li></ul><ul><li>the unmet medical need </li></ul>
New Drug Discovery and Development (Timelines) DISCOVERY/SCREENING SYNTHESIS AND PURIFICATION ANIMAL TESTING PHASE II PHAS...
5000 compounds  evaluated Phase-I 20-100 healthy volunteers 0 2 4 6 8 10 12 16 14 Years Phase-II 100-500 patient volunteer...
Cost of bringing a new drug to the market is 800M to 1B US$
NCE In vitro In vitro Acute tox DRUG Insoluble New Drug Discovery is like snakes and ladder failure is the norm Active
Understand Disease & Identify unmet needs Select Mechanism/ Target Design NCEs & Screens Virtual  Screening Synthesize  NC...
 
Attributes of a successful target <ul><li>Provide adequate selectivity & spectrum </li></ul><ul><li>Essential for growth o...
 
 
Microarray chip
Image from Gene-Chips (Microarray)
 
TARGET  IDENTIFICATION  & VALIDATION R&D Technology HIT IDENTIFICATION  LEAD SEARCH  & OPTIMIZATION CANDIDATE  SELECTION  ...
Next advance will be availability of complete genomic sequences from  multiple strains of a single pathogen .
Genomic sequence information <ul><li>Selectivity </li></ul><ul><li>Spectrum </li></ul><ul><li>Functionality </li></ul><ul>...
Pre clinical studies Broad Aim <ul><li>Efficacy:  in vitro  and  in vivo </li></ul><ul><li>Safety in animals </li></ul>
Pre clinical studies Objectives <ul><li>To demonstrate anti infective activity against target pathogens </li></ul><ul><li>...
Pre clinical studies what needs to be done <ul><li>In vitro  activity against target and other pathogens </li></ul><ul><li...
Efficacy studies
In vitro  tests <ul><li>Antimicrobial spectrum of activity </li></ul><ul><ul><ul><li>MIC  50 , MIC  90 , G.M. </li></ul></...
IFs Elongation Tetracyclines Macrolides, Streptogramins Protein Biosynthesis Rifampicin, Aminoglycosides 30S subunit 50S s...
RBx7644 IFs Initiation Complex not formed Site of action of RBx 7644 Protein synthesis inhibition  at a novel site 30S sub...
In vivo  evaluation <ul><li>Objective:   </li></ul><ul><ul><li>To yield information on the NCE’s biological activity again...
In vivo  efficacy models <ul><li>Screening </li></ul><ul><li>Monoparametric </li></ul><ul><li>Ex vivo </li></ul><ul><li>Di...
In vitro  -  In vivo  correlation of antimicrobial activity <ul><li>In vitro In vivo Frequency (%) </li></ul><ul><li>- - 4...
Reasons for  in vivo  inactivity of  in vitro  active compounds <ul><li>Microbiological: </li></ul><ul><ul><li>Metabolic s...
Drug ability features <ul><li>Lipinski’s rule of 5 </li></ul><ul><ul><li>Poor absorption or permeation more likely if </li...
SAR
Regulatory studies
Investigational New Drug  (IND) application <ul><li>Toxicity studies in animals: Acute and sub-acute toxicity studies, in ...
Schedule Y Drugs and Cosmetics Act <ul><li>Animal toxicology : </li></ul><ul><ul><li>3.1 Acute Toxicology : at least 2 spe...
 
 
Yes, <ul><li>Drugs are required to meet  </li></ul><ul><li>the unmet medical need </li></ul>                         
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Making Of An Antibiotic 2009

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Preclinical journey of a new antibiotic

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Transcript of "Making Of An Antibiotic 2009"

  1. 1. Making of an antibiotic Pre Clinical Journey Dr. Ashok Rattan Chief Executive, Fortis Clinical Research Ltd., Adviser, Religare SRL Diagnostics in Fortis / Escorts Hospitals, Delhi & NCR
  2. 2. We are overwhelmed as it is, with an infinite abundance of vaunted medicaments; and here they add a new one….. Thomas Sydenham, MD (1624 - 1689)
  3. 3. Do we really need new anti- infectives ? <ul><li>> 80 efficacious agents available to treat ALL bacterial ; most fungal infections & some viral infections </li></ul><ul><li>but </li></ul><ul><li>limitation of spectrum of available drugs </li></ul><ul><li>PK drawbacks: either oral or IV </li></ul><ul><li>Toxicity: acute or sub-acute </li></ul><ul><li>Rapid development of drug resistance </li></ul>
  4. 4. Yes, <ul><li>Drugs are required to meet </li></ul><ul><li>the unmet medical need </li></ul>
  5. 5. New Drug Discovery and Development (Timelines) DISCOVERY/SCREENING SYNTHESIS AND PURIFICATION ANIMAL TESTING PHASE II PHASE I SHORT-TERM PHASE III LONG-TERM PHASE IV ADVERSE REACTION SURVEILLANCE PRODUCT DEFECT REPORTING PRE-CLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW POST-MARKETING 24 + 18 months. AVG: 5 YEARS AVG: 12 MOS. IND NDA APPROVAL
  6. 6. 5000 compounds evaluated Phase-I 20-100 healthy volunteers 0 2 4 6 8 10 12 16 14 Years Phase-II 100-500 patient volunteers Phase-III 1000-5000 patient volunteers Review and approval by Food & Drug Administration 1 Compound approved 5 INDs Discovery and preclinical testing Source: Tufts Centre For Study Of Drug Development in C&EN, June 2000 Bringing a new drug to the market can take 15 years
  7. 7. Cost of bringing a new drug to the market is 800M to 1B US$
  8. 8. NCE In vitro In vitro Acute tox DRUG Insoluble New Drug Discovery is like snakes and ladder failure is the norm Active
  9. 9. Understand Disease & Identify unmet needs Select Mechanism/ Target Design NCEs & Screens Virtual Screening Synthesize NCEs Convert Lead-to-IND Candidate New Drug Discovery Road Map Preclinical work-up IND directed regulatory studies Convert Hit-to-Lead Screen/ Identify Hit
  10. 11. Attributes of a successful target <ul><li>Provide adequate selectivity & spectrum </li></ul><ul><li>Essential for growth or virulence </li></ul><ul><li>HTS assay development should be possible </li></ul>
  11. 14. Microarray chip
  12. 15. Image from Gene-Chips (Microarray)
  13. 17. TARGET IDENTIFICATION & VALIDATION R&D Technology HIT IDENTIFICATION LEAD SEARCH & OPTIMIZATION CANDIDATE SELECTION GLP PHASE PHASE I-II PHASE II - III EXPLORATORY RESEARCH DRUG DISCOVERY DRUG PROFILING PRE- DEVELOPMENT DEVELOPMENT GENOMICS PROTEOMICS PHARMACOGENETICS BIOINFORMATICS HTS ASSAY DEVELOPMENT SUBSTANCE LIBRARY MOLECULAR MODELING COMBINATORIAL CHEMISTRY IN VITRO & ANIMAL PHARMACOLOGY TOXICOLOGY NEW FORMULATION PILOT PLANT PHARMACOGENETICS DATA MINING DATA BASE
  14. 18. Next advance will be availability of complete genomic sequences from multiple strains of a single pathogen .
  15. 19. Genomic sequence information <ul><li>Selectivity </li></ul><ul><li>Spectrum </li></ul><ul><li>Functionality </li></ul><ul><li>Essentiality </li></ul>
  16. 20. Pre clinical studies Broad Aim <ul><li>Efficacy: in vitro and in vivo </li></ul><ul><li>Safety in animals </li></ul>
  17. 21. Pre clinical studies Objectives <ul><li>To demonstrate anti infective activity against target pathogens </li></ul><ul><li>To examine culture conditions that may modify activity </li></ul><ul><li>To determine interaction with other drugs </li></ul><ul><li>To provide information of mechanism and potential for resistance development </li></ul><ul><li>To determine therapeutic index </li></ul><ul><li>To suggest dose and surrogate markers of efficacy in man </li></ul>
  18. 22. Pre clinical studies what needs to be done <ul><li>In vitro activity against target and other pathogens </li></ul><ul><li>In vivo efficacy </li></ul><ul><li>Acute and sub-acute toxicity in 2 species </li></ul><ul><li>Genotoxicity </li></ul><ul><li>PK and TK analysis </li></ul><ul><li>Formulation and stability </li></ul><ul><li>Synthesis of NCE under GMP conditions </li></ul>
  19. 23. Efficacy studies
  20. 24. In vitro tests <ul><li>Antimicrobial spectrum of activity </li></ul><ul><ul><ul><li>MIC 50 , MIC 90 , G.M. </li></ul></ul></ul><ul><ul><ul><li>Kinetic kill of bacteria </li></ul></ul></ul><ul><ul><ul><li>Cidal or static </li></ul></ul></ul><ul><li>Effect of medium, pH, inoculum, serum </li></ul><ul><li>Interaction with other antibiotics </li></ul><ul><li>Frequency and selection of resistance </li></ul><ul><li>Mechanism of action </li></ul>
  21. 25. IFs Elongation Tetracyclines Macrolides, Streptogramins Protein Biosynthesis Rifampicin, Aminoglycosides 30S subunit 50S subunit AUGCCGGGUUAC UAA 5’ 3’ mRNA AUGCCGGGUUAC UAA 5’ 3’ 30S + mRNA fMet-tRNA AUGCCGGGUUAC UAA 5’ 3’ 70S Initiation Complex EFs Elongation factors + t-RNAs Peptide product
  22. 26. RBx7644 IFs Initiation Complex not formed Site of action of RBx 7644 Protein synthesis inhibition at a novel site 30S subunit 50S subunit AUGCCGGGUUAC UAA 5’ 3’ mRNA AUGCCGGGUUAC UAA 5’ 3’ 30S + mRNA fMet-tRNA
  23. 27. In vivo evaluation <ul><li>Objective: </li></ul><ul><ul><li>To yield information on the NCE’s biological activity against representative microbes </li></ul></ul><ul><ul><li>PK/PD characteristics </li></ul></ul><ul><ul><li>Toxicity </li></ul></ul>
  24. 28. In vivo efficacy models <ul><li>Screening </li></ul><ul><li>Monoparametric </li></ul><ul><li>Ex vivo </li></ul><ul><li>Discriminatory </li></ul>
  25. 29. In vitro - In vivo correlation of antimicrobial activity <ul><li>In vitro In vivo Frequency (%) </li></ul><ul><li>- - 45.3 </li></ul><ul><li>- + 0.3 </li></ul><ul><li>+ - 39.6 </li></ul><ul><li>+ + 14.8 </li></ul><ul><li>54.4 15.1 </li></ul>
  26. 30. Reasons for in vivo inactivity of in vitro active compounds <ul><li>Microbiological: </li></ul><ul><ul><li>Metabolic state of bacteria (dormant bacteria) </li></ul></ul><ul><ul><li>Presence of nonpathogenic inactivating bacteria </li></ul></ul><ul><li>PK </li></ul><ul><ul><li>Poor oral absorption or rapid excretion </li></ul></ul><ul><ul><li>Rapid metabolism </li></ul></ul><ul><ul><li>Inability to reach target site - CSF, intracellular </li></ul></ul><ul><li>Biological: </li></ul><ul><ul><li>Antagonistic environment - pH </li></ul></ul><ul><li>Toxicity: </li></ul><ul><ul><li>Effective dose cannot be given </li></ul></ul>
  27. 31. Drug ability features <ul><li>Lipinski’s rule of 5 </li></ul><ul><ul><li>Poor absorption or permeation more likely if </li></ul></ul><ul><ul><ul><li>More than 5 H bond donors </li></ul></ul></ul><ul><ul><ul><li>Mol Wt more than 500 </li></ul></ul></ul><ul><ul><ul><li>cLog P more than 5 </li></ul></ul></ul><ul><ul><ul><li>Sum of N and O more than 10 </li></ul></ul></ul><ul><li>Physo-chemical property </li></ul><ul><ul><li>Solubility, stability </li></ul></ul><ul><li>In vitro ADME Tox screen </li></ul><ul><ul><li>Permeability, cell based toxicity, cyp 450 inhibition or induction, hERG potential, Plasma Protein Binding </li></ul></ul>
  28. 32. SAR
  29. 33. Regulatory studies
  30. 34. Investigational New Drug (IND) application <ul><li>Toxicity studies in animals: Acute and sub-acute toxicity studies, in rodents & non-rodents and Ames mutagenicity, should be given in a tabular form indicating species…. </li></ul><ul><li>(This should be given in Appendix III as per Appendices III and IV of Schedule Y) </li></ul>
  31. 35. Schedule Y Drugs and Cosmetics Act <ul><li>Animal toxicology : </li></ul><ul><ul><li>3.1 Acute Toxicology : at least 2 species </li></ul></ul><ul><ul><li>3.2 Long term toxicity : 2 mammalian species, of which one should be a non rodent </li></ul></ul><ul><ul><li>3.3 Reproduction studies </li></ul></ul><ul><ul><li>3.4 Local toxicity </li></ul></ul><ul><ul><li>3.5 Mutagenicity and Carcinogenicity </li></ul></ul><ul><li>Animal pharmacology </li></ul><ul><ul><li>Dose response, ED 50 </li></ul></ul>
  32. 38. Yes, <ul><li>Drugs are required to meet </li></ul><ul><li>the unmet medical need </li></ul>                       
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