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Preclinical journey of a new antibiotic
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Making of an antibioticPre 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)
DIS
CO
VE
RY
/SC
RE
EN
ING
SYNTHESIS AND PURIFICATION
ANIMAL TESTING
PHASE II
PHASE I
SHORT-TERM
PHASE III
LONG-TERM
PHASE IV
ADVERSEREACTION
SURVEILLANCEPRODUCT DEFECT
REPORTING
PRE-CLINICALRESEARCH 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 1614
Years
Phase-II100-500 patient volunteers
Phase-III
1000-5000 patient volunteers
Review and approval byFood & Drug Administration
1Compoundapproved
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 ladderfailure is the norm
Active
UnderstandDisease & Identify
unmet needs
SelectMechanism/
Target
DesignNCEs &Screens
Virtual Screening
Synthesize NCEs
ConvertLead-to-IND
Candidate
New Drug Discovery Road MapPreclinical work-up
IND directed regulatory studies
ConvertHit-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 studiesBroad Aim
• Efficacy: in vitro and in vivo
• Safety in animals
Pre clinical studiesObjectives
• 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 studieswhat 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
30S subunit
50S subunit
AUGCCGGGUUACUAA5’ 3’
mRNA
IFs AUGCCGGGUUACUAA5’ 3’
30S + mRNA fMet-tRNA
AUGCCGGGUUACUAA5’ 3’
70S Initiation Complex
EFs
Elongation factors + t-RNAs
Elongation
Peptide product
Tetracyclines
Macrolides, Streptogramins
Protein BiosynthesisProtein Biosynthesis
Rifampicin, Aminoglycosides
RBx7644RBx7644
30S subunit
50S subunit
AUGCCGGGUUACUAA5’ 3’
mRNA
IFs AUGCCGGGUUACUAA5’ 3’
30S + mRNA fMet-tRNA
Initiation Complex Initiation Complex not formednot formed
Site of action of RBx 7644Site of action of RBx 7644
Protein synthesis inhibition at a novel site
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 YDrugs 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, ED50
Yes,
Drugs are required to meet
the unmet medical need
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