Biology Services
Upcoming SlideShare
Loading in...5
×
 

Like this? Share it with your network

Share

Biology Services

on

  • 2,761 views

Part of the MaRS Best Practices Series - Pre-Clinical development workshop

Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/

Speaker: Randy Jones, VP Biology Sciences, Ricerca BioSciences

Statistics

Views

Total Views
2,761
Views on SlideShare
2,760
Embed Views
1

Actions

Likes
1
Downloads
96
Comments
0

1 Embed 1

http://www.slideshare.net 1

Accessibility

Upload Details

Uploaded via as Adobe PDF

Usage Rights

CC Attribution-NonCommercial-NoDerivs LicenseCC Attribution-NonCommercial-NoDerivs LicenseCC Attribution-NonCommercial-NoDerivs License

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Biology Services Presentation Transcript

  • 1. Biology Services Randy Jones, D.V.M., Ph.D. Diplomate A.B.V.T. & A.B.T. Vice President Biology Services Ricerca Biosciences, LLC May 23, 2007
  • 2. Introduction • Animal models screen drug candidates for potential therapeutic efficacy • Confounded by species of animal, metabolism, pharmacokinetics, organ system anatomy, and physiology • An initial opportunity to integrate biology and chemistry • Anti-infective, oncology screening, and anti-inflammation models are likely to remain important for development of drug candidates for an aging population • Established disease models require less time and development expense but may lack specificity • Brief application of anti-infectivity models, in vivo anti-tumor assays, and anti-inflammatory models will be presented
  • 3. Biotech Business Model Is the Bio-Entrepreneur more successful than Pharma at drug development? • Typical biotech customer proceeds cautiously with one or two projects and moves to combinations of biology and chemistry • Need to develop their “one-and-only” lead into an IND • Cash Flow – “do or die” • Smaller organizations – fewer layers
  • 4. Overview Animal models of human disease are used to screen drug candidates for potential therapeutic efficacy focusing on pharmacology and mechanism of action • Ethical considerations support the judicious use of animals prior to first-in-human use • Drugs are not used to treat normal people • Drug candidates are tested for toxicity on physiologically normal, juvenile animals (rodent & non-rodent) • Pharmacology vs toxicology endpoints • Mechanism of action – homology, specificity….
  • 5. Overview (Continued) The predictive nature of the model and its potential to extrapolate to a human disease is impacted by: • Species of animal • Metabolism – constitutive and inducible capacity • Pharmacokinetics – drug-ability • Organ system anatomy • Physiology
  • 6. Metabolite Profile %Loss of Parent Compound 120 Risk Management 100 % Loss of Parent 80 60 Cyn vs Rh ! 40 20 Teenage athlete vs ! 0 0 5 10 15 20 25 30 35 Geriatric poly-pharmacy Incubation Time (min.) Dog Cyn Monkey Rh Monkey Human Mouse Rat Therapeutic index ! %Increase in Metabolite Formation Clinical Indication ! % Increase in Metabolite 60 Bimodal or uniform ! 50 pharmacogenomics 40 30 FDA/ICH guidelines 20 ! 10 0 0 5 10 15 20 25 30 35 Time (min.) Dog Cyn Monkey Rh Monkey Human Mouse Rat
  • 7. Pharmacokinetics Rapid In Vivo screening Parent (Pro-drug) 700 Pharmacokinetic Parameters 600 500 ng/ 400 IV mL • AUC, volume of distribution, 300 oral 200 100 half-life, Cmax, clearance, 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hr) bioavailability Active Metabolite 10000 Test Material Requirements 8000 ng/ 6000 IV mL oral 4000 • Limited amount 2000 0 0 2 4 6 8 10 12 14 16 18 20 22 24 • Radiolabel not necessary Time (hr)
  • 8. Integration of Biology and Chemistry • Saltability • Crystallinity - HS-PLM, XRD, DSC, TGA • Hygroscopicity - Hydration states • Solubility • Stability • Polymorphism • Powder Properties
  • 9. Why is this a Problem? Physical-chemical • properties of each form are different Solubility • Dissolution Rate • The intermolecular • Chemical Stability forces in a solid • contribute to the Physical Stability • properties of the solid Processability • Rate of Elimination • Bioavailability •
  • 10. Animal Models In Vivo Efficacy • Anti-infective • Anti-cancer • Anti-inflammation • Others • Obesity • Diabetes • Gene Therapy Work with Clients to Customize Models Dedicated BSL-2 Animal Rooms
  • 11. Animal Models of Infection (Anti-Infective) Infectious agent introduced & the ability of the drug candidate to relieve the experimental disease process is evaluated • Thigh Infection Model – bacterial agents (mouse or rat) Neutropenic animal, end points and target tissues Antimicrobial efficacy of the drug candidate – plate count data CFU/gram thigh tissue Pharmacokinetics Clinical pathology • In Vitro Assay Support • Minimum inhibitory concentration, minimum bactericidal concentration, time-kill kinetic assays
  • 12. Animal Models of Infection (Anti-Infective) An infectious agent is introduced and the ability of the drug candidate to relieve the experimental disease process is evaluated • Mouse Sepsis Model – Staphylococcus aureus (MSSA and MRSA), S. pneumonia, E. Coli, P aeruginosa, Candida albicans (anti-fungal) – End points and target tissues 100 90 80 70 ---- Infectedcontrol control Infected ---- Vancomycin 60 Vancomycin % survival ---- TA-1 (solution) REP0897 (solution) 50 ---- TA-1 (suspension) REP0897 (suspension) REP0318 (solution) ---- TA-2 (solution) 40 REP0318 (suspension) ---- TA-2 (suspension) 30 20 10 0 -1 5 11 17 23 29 35 Day
  • 13. Oncology Screening Models (Anti-cancer) In Vivo Anti-tumor Assays (Xenograft models) • Severe combined immunodeficient (SCID) mice, single subcutaneous injection x 7 day for tumor induction followed by drug candidate dosing by applicable route and dose levels x 7 days. Currently established tumor models at Ricerca: Cell Line Species Cancer Type C-33A human cervical Ramos human B lymphocyte PC-3 human prostate A-549 human lung, non-small cell HL-60 human leukemia, PML B16-F0 mouse melanoma • End points - tumor size, histopathology of the induced lesion, clinical pathology • Pharmacokinetics
  • 14. Oncology Screening Models (Anti-cancer) In Vitro Assays • Anti-proliferation • Acute cytotoxicity – lethality or induction of apoptosis 100 100 80 80 % Inhibition % Inhibition 60 60 40 40 20 20 0 0 -200.10 1.00 10.00 100.00 1000.00 -200.10 1.00 10.00 100.00 Conc (!M) Conc (!M)
  • 15. Anti-Inflammation Model An acute efficacy screening model to evaluate impact on the inflammatory response: LPS Induction of TNF! Release in Balb-c Mice • Drug candidate administered orally, intraperitoneal, sub-cutaneously • Lipopolysaccharide (LPS) dosed IP - optimized to provide maximal release of TNF! • End points – serum/plasma TNF! by ELISA – Pharmacokinetic satellite group – Biomarkers
  • 16. Effect on LPS Induced TNF! Release in Mice by Single Oral Dose of Test Article Percent reduction from LPS control 100% 90% 1 hour 80% between 70% oral dose 60% and LPS dose 50% 4 Hours 40% between 30% oral dose and LPS 20% dose 10% 0% 0 0 ,10 0 0 2, 1 4, 1 1,1 3,1 PC TA TA TA TA Test Article dosed and dose administered (mg/kg)
  • 17. Summary • Animal models screen drug candidates for potential therapeutic efficacy • Confounded by species of animal, metabolism, pharmacokinetics, organ system anatomy, and physiology • An initial opportunity to integrate biology and chemistry • Anti-infectivity models • Anti-tumor assays • Anti-inflammatory models
  • 18. Thank you! Ricerca Contacts Ann L. O’Leary, Ph.D. Manager, Animal Models/Microbiology 440-357-3561 oleary_a@ricerca.com Prabu Devanesan, Ph.D. Manager, In Vitro DMPK 440-357-3106 devanesan_p@ricerca.com Andrea Hubbell Scientist, In Vitro DMPK 440-357-3753 hubbell_a@ricerca.com
  • 19. Biology Services Randy Jones, D.V.M., Ph.D. Diplomate A.B.V.T. & A.B.T. Vice President Biology Services Ricerca Biosciences, LLC February 5, 2007