Making Of An Antibiotic 2009
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Making Of An Antibiotic 2009

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Preclinical journey of a new antibiotic

Preclinical journey of a new antibiotic

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Making Of An Antibiotic 2009 Making Of An Antibiotic 2009 Presentation Transcript

  • 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
  • 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)
  • Do we really need new anti- infectives ?
    • > 80 efficacious agents available to treat ALL bacterial ; most fungal infections & some viral infections
    • but
    • limitation of spectrum of available drugs
    • PK drawbacks: either oral or IV
    • Toxicity: acute or sub-acute
    • Rapid development of drug resistance
  • Yes,
    • Drugs are required to meet
    • the unmet medical need
  • 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
  • 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
  • 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 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
  •  
  • Attributes of a successful target
    • Provide adequate selectivity & spectrum
    • Essential for growth or virulence
    • HTS assay development should be possible
  •  
  •  
  • Microarray chip
  • Image from Gene-Chips (Microarray)
  •  
  • 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
  • Next advance will be availability of complete genomic sequences from multiple strains of a single pathogen .
  • Genomic sequence information
    • Selectivity
    • Spectrum
    • Functionality
    • Essentiality
  • Pre clinical studies Broad Aim
    • Efficacy: in vitro and in vivo
    • Safety in animals
  • Pre clinical studies Objectives
    • To demonstrate anti infective activity against target pathogens
    • To examine culture conditions that may modify activity
    • To determine interaction with other drugs
    • To provide information of mechanism and potential for resistance development
    • To determine therapeutic index
    • To suggest dose and surrogate markers of efficacy in man
  • Pre clinical studies what needs to be done
    • In vitro activity against target and other pathogens
    • In vivo efficacy
    • Acute and sub-acute toxicity in 2 species
    • Genotoxicity
    • PK and TK analysis
    • Formulation and stability
    • Synthesis of NCE under GMP conditions
  • Efficacy studies
  • In vitro tests
    • Antimicrobial spectrum of activity
        • MIC 50 , MIC 90 , G.M.
        • Kinetic kill of bacteria
        • Cidal or static
    • Effect of medium, pH, inoculum, serum
    • Interaction with other antibiotics
    • Frequency and selection of resistance
    • Mechanism of action
  • 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
  • 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
  • In vivo evaluation
    • Objective:
      • To yield information on the NCE’s biological activity against representative microbes
      • PK/PD characteristics
      • Toxicity
  • In vivo efficacy models
    • Screening
    • Monoparametric
    • Ex vivo
    • Discriminatory
  • In vitro - In vivo correlation of antimicrobial activity
    • In vitro In vivo Frequency (%)
    • - - 45.3
    • - + 0.3
    • + - 39.6
    • + + 14.8
    • 54.4 15.1
  • Reasons for in vivo inactivity of in vitro active compounds
    • Microbiological:
      • Metabolic state of bacteria (dormant bacteria)
      • Presence of nonpathogenic inactivating bacteria
    • PK
      • Poor oral absorption or rapid excretion
      • Rapid metabolism
      • Inability to reach target site - CSF, intracellular
    • Biological:
      • Antagonistic environment - pH
    • Toxicity:
      • Effective dose cannot be given
  • Drug ability features
    • Lipinski’s rule of 5
      • Poor absorption or permeation more likely if
        • More than 5 H bond donors
        • Mol Wt more than 500
        • cLog P more than 5
        • Sum of N and O more than 10
    • Physo-chemical property
      • Solubility, stability
    • In vitro ADME Tox screen
      • Permeability, cell based toxicity, cyp 450 inhibition or induction, hERG potential, Plasma Protein Binding
  • SAR
  • Regulatory studies
  • Investigational New Drug (IND) application
    • 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….
    • (This should be given in Appendix III as per Appendices III and IV of Schedule Y)
  • Schedule Y Drugs and Cosmetics Act
    • Animal toxicology :
      • 3.1 Acute Toxicology : at least 2 species
      • 3.2 Long term toxicity : 2 mammalian species, of which one should be a non rodent
      • 3.3 Reproduction studies
      • 3.4 Local toxicity
      • 3.5 Mutagenicity and Carcinogenicity
    • Animal pharmacology
      • Dose response, ED 50
  •  
  •  
  • Yes,
    • Drugs are required to meet
    • the unmet medical need