Presented by:
Ms. Suruchi Ramkumar Sharma
F.Y. M.Pharm
Under the guidance of:
Dr. (Mrs.) Vaishali Dixit
M.E.T Institute of...
 Definition:
The US FDA defines a biomarker as a
characteristic i.e.
objectively measured & evaluated as an
indicator of
...
• It can be specific cells, molecules or genes,
gene products, enzymes or hormones.
• Helps in early diagnosis, disease pr...
4
Disease – related
Biomarkers
Drug – related
Biomarkers
Risk indicator / predictive
biomarkers
Indicate effectiveness of a
...
6
7
Based on
Characteristics
8
9
Biomarkers validated by genetic and
molecular biology methods can be classified
into three types:
 Type 0 - Natural histo...
Discovery
of
Molecular
Biomarkers
ASSAY TECHNIQUES 11
In Toxicology & Clinical trials -
• In vivo monitoring
• Early detection of metabolic changes
• Detection of organ-specifi...
 Important issues to remember:
• Cell types differ in susceptibility to toxic agents
• One organ – many cell types
• Cell...
 Localization of damage:
Centrilobular (zone 3)
• Most hepatotoxicants (CCl4, APAP)
• Less oxygen + high P450 conc.
Perip...
Cholestatic injury Cytotoxic injury Altered hepatic
function
Alkaline Phosphatase
[AP, ALP]
Aspartate
aminotransferase
[AS...
16
Serum Indicators Urine Indicators
Blood Urea Nitrogen
(BUN)
Physical
characteristics
Chemical
Characteristics
Blood Creati...
 Develop new biomarkers that predict toxicity
in the preclinical development of NCEs early
in the drug development proces...
19
 Acetaminophen (APAP) is responsible for 50%
of all drug-induced acute liver failure.
• High-throughput LC/MS-based metab...
 NMR-based approach to investigate toxicity
induced by Bay41-4109, an anti-hepatitis B
virus compound.
• Biomarker : Fatt...
 UPLC/MS to investigate toxicity by CCl4 and α-
napthylisothiocyanate.
• Biomarker : Changes in bile acids.
 Integration...
 NMR and HPLC-TOF/MS approach for
Cyclosporin A in a rodent model.
• Biomarker : Elevated levels of urinary
glucose, acet...
 Gentamicin in SD rats,
• Biomarker : Increased urinary level of
glucose and decreased level of TMAO by NMR
with decrease...
 Cisplatin in mice,
• Biomarker : Altered urinary levels of glucose,
amino acids and Krebs cycle intermediates
that prece...
 Used in the drug development process
• Early drug development studies
e.g. used in phase I study for establishing
doses ...
27
28
Clinical biomarker in Lung Cancer: Volumetric growth analysis
of lesions in high resolution CT.
29
30
 A new face in diagnostics, therapeutics &
drug development.
 Potential to encourage innovation, improve
efficiency, sav...
• Biomarkers in toxicology, Timbrell J. A.,
Volume 129, Issue 1, Pages 1-12, 7 August
1998.
• Metabolomics approaches for ...
• Clinical Biomarkers in drug discovery and
development, Richard Frank and Richard
Hargreaves, Volume 2, Pages 566-580, Ju...
34
35
DISCUSSION
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Biomarkersintoxicologyandclinicalresearch 120726101025-phpapp01

  1. 1. Presented by: Ms. Suruchi Ramkumar Sharma F.Y. M.Pharm Under the guidance of: Dr. (Mrs.) Vaishali Dixit M.E.T Institute of Pharmacy, Bandra (W) 12-Mar-2012
  2. 2.  Definition: The US FDA defines a biomarker as a characteristic i.e. objectively measured & evaluated as an indicator of normal biologic, pathogenic or pharmacologic responses to therapeutic intervention. 2
  3. 3. • It can be specific cells, molecules or genes, gene products, enzymes or hormones. • Helps in early diagnosis, disease prevention, drug target identification, drug response etc. Examples • serum LDL for cholesterol • blood pressure for stroke • C-reactive protein (CRP) for inflammation 3
  4. 4. 4
  5. 5. Disease – related Biomarkers Drug – related Biomarkers Risk indicator / predictive biomarkers Indicate effectiveness of a drug in a specific patient Diagnostic & prognostic biomarker How the patient’s body will process it 5
  6. 6. 6
  7. 7. 7
  8. 8. Based on Characteristics 8
  9. 9. 9
  10. 10. Biomarkers validated by genetic and molecular biology methods can be classified into three types:  Type 0 - Natural history markers  Type 1 - Drug activity markers  Type 2 - Surrogate markers 10
  11. 11. Discovery of Molecular Biomarkers ASSAY TECHNIQUES 11
  12. 12. In Toxicology & Clinical trials - • In vivo monitoring • Early detection of metabolic changes • Detection of organ-specific effects • Establishment of “NO EFFECT” level • Determination of toxic mechanism 12
  13. 13.  Important issues to remember: • Cell types differ in susceptibility to toxic agents • One organ – many cell types • Cellular injury vs. organ function impairment • Oxygen concentration gradients • Metabolizing enzymes (e.g., Cytochrome P450) concentration gradients 13
  14. 14.  Localization of damage: Centrilobular (zone 3) • Most hepatotoxicants (CCl4, APAP) • Less oxygen + high P450 conc. Periportal (zone 1) • Phosphorus, aflatoxin, allyl alcohol • High oxygen + highest dose at site Midzonal (zone 2) – • Beryllium • Massive necrosis - iproniazid, MAOI Liver Lobule 14
  15. 15. Cholestatic injury Cytotoxic injury Altered hepatic function Alkaline Phosphatase [AP, ALP] Aspartate aminotransferase [AST] Creatine phosphokinase [CPK] 5’-Nucleotidase [5-NT] Lactate Dehydrogenase [LDH] Choline Esterase [ChE] (acetylcholine esterase and butyrylcholine esterase)γ - Glutamyl Transpeptidase [GGT] Alanine aminotransferase [ALT] Total Serum Bile Acids Ornithine carbamyl transferase [OCT] Decreased dye clearance •Sulfobromophthalein •Indocyanine greenPlasma Bilirubin Alanine aminotransferase [SDH] 15
  16. 16. 16
  17. 17. Serum Indicators Urine Indicators Blood Urea Nitrogen (BUN) Physical characteristics Chemical Characteristics Blood Creatinine Color/turbidity (RBC’s, bilirubin) Urinary protein – tubular (low MW) or glomerular (high MW) Volume Urinary glucose – no elevation of blood glucose but glucosuria (tubular) Osmolality Urinary brush border enzymes (ALP, AST, GGT) 17
  18. 18.  Develop new biomarkers that predict toxicity in the preclinical development of NCEs early in the drug development process and are translatable to the clinic.  To reduce the time and cost associated with drug discovery and approval.  Metabolic profiling methods used are based on metabolomics and/ or metabonomics.  Metabolomics is especially important in the early ADME/Tox stage of drug testing. 18
  19. 19. 19
  20. 20.  Acetaminophen (APAP) is responsible for 50% of all drug-induced acute liver failure. • High-throughput LC/MS-based metabolomic assays rapidly investigate APAP and its metabolites excretion profile in urine from rats. • Biomarker : Changes in the SAMe concentrations inversely proportional with urinary APAP–NAC concentration. 20
  21. 21.  NMR-based approach to investigate toxicity induced by Bay41-4109, an anti-hepatitis B virus compound. • Biomarker : Fatty acid metabolism disorder and mitochondrial dysfunction.  GC/MS was used to study carbon tetrachloride-induced acute liver injury in mice. • Biomarker : Elevated levels of maleate and several fatty acids in the liver. 21
  22. 22.  UPLC/MS to investigate toxicity by CCl4 and α- napthylisothiocyanate. • Biomarker : Changes in bile acids.  Integration of OMICS: • Metabolomics + transcriptomics liver samples of two mouse strains regulated glutamate and glutamine networks diabetes and obesity. • Metabolomic + proteomics liver samples of CD1 mice acute hepatotoxicity induced by valproic acid altered glucose levels. 22
  23. 23.  NMR and HPLC-TOF/MS approach for Cyclosporin A in a rodent model. • Biomarker : Elevated levels of urinary glucose, acetate, trimethylamine, succinate and reduced levels of urinary TMAO + decreased levels of kynurenic acid, xanthurenic acid, citric acid and riboflavin. • Biomarker : Increased levels of glucose, hydroxybutyrate, creatine, creatinine, TMAO and decreased concentration of glutathione. 23
  24. 24.  Gentamicin in SD rats, • Biomarker : Increased urinary level of glucose and decreased level of TMAO by NMR with decreases in xanthurenic and kynurenic acids and changes in sulfation patterns by MS. Glucosuria. • Biomarker : UPLC/MS showed increase in urinary levels of 6-hydroxymelatonin. 24
  25. 25.  Cisplatin in mice, • Biomarker : Altered urinary levels of glucose, amino acids and Krebs cycle intermediates that preceded changes in serum creatinine.  Chronic toxicity testing of nephrotoxicants: gentamicin, cisplatin and tobramycin in SD rats, non targetted analysis after 1, 5 and 28 days dosing caused Aminoaciduria (marker of kidney damage) due to decreased renal reabsorption. 25
  26. 26.  Used in the drug development process • Early drug development studies e.g. used in phase I study for establishing doses and dosing regimen for future phase II studies. • Safety studies e.g. APAP induced hepatotoxicity study • Proof of concept studies • Molecular profiling 26
  27. 27. 27
  28. 28. 28
  29. 29. Clinical biomarker in Lung Cancer: Volumetric growth analysis of lesions in high resolution CT. 29
  30. 30. 30
  31. 31.  A new face in diagnostics, therapeutics & drug development.  Potential to encourage innovation, improve efficiency, save costs.  Potential to encourage innovation, improve efficiency, save costs, and gain research organizations a valuable advantage.  The ultimate promise of a future towards personalized healthcare. 31
  32. 32. • Biomarkers in toxicology, Timbrell J. A., Volume 129, Issue 1, Pages 1-12, 7 August 1998. • Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity, Beger R. D., Volume 243, Issue 2, Pages 154–166, March 2010. • Biomarkers of Toxicity, NTP Workshop, Workshop report, September 20-21, 2006. 32
  33. 33. • Clinical Biomarkers in drug discovery and development, Richard Frank and Richard Hargreaves, Volume 2, Pages 566-580, July 2003. • Biomarkers and surrogate endpoints, Clinical research and applications, G. D. Downing, Elsevier (2000). • Biomarkers in Drug Development – A CRO Perspective, John Allison & Steve Brooks, pages 15-19, 2004. 33
  34. 34. 34
  35. 35. 35 DISCUSSION

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