The document discusses various animal models used to screen drug candidates for therapeutic efficacy prior to human trials. It summarizes several key animal models: [1] Anti-infective models evaluate a drug's ability to relieve infection in animals; [2] Anti-cancer xenograft models test drugs' effects on tumor size and growth in mice; [3] Anti-inflammatory models assess a drug's impact on reducing inflammatory responses in mice. The models are useful but limited precursors to human studies due to interspecies differences in anatomy, physiology and metabolism.
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Biology Services
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
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