This document discusses the use of animal models in pharmaceutical research and their limitations. It describes how animal doses are converted to human equivalent doses using allometric scaling based on body surface area. The document also discusses alternative approaches like computer-based modelling and physiologically-based pharmacokinetic/pharmacodynamic modelling to predict human responses based on data from animal and other preclinical studies in order to reduce risks in early human trials. Several companies that have implemented such modelling approaches are also mentioned.

1. Moving from
Animal Model
to the Clinic
Dr. Govind Girase
UDIRT, MUHS
1st Year 2012.
Saturday Club
“A Complimentary Market Research Study”
Author: Insight Pharma Reports
Publisher : Cambridge Healthtech Institute

2. USE OF EXTENSIVE TECHNOLOGIES IN
PHARMACEUTICAL RESEARCH
To improve operational
efficacy of Drug Development
Economical pressure in drug
development
To Save Drug development
Time

3. Risk of Administering Unsafe drug or unsafe levels of drugs in
Humans
To study expected Therapeutic outcome Animal Model were
Introduced
Guidelines Drafted how to Estimate safe starting Dose with
respect to
(NOEL,BSA-CF, PAD,NOAEL/MTD)
Conversion of Animal Dose to Human Equivalent Dose
(HED, MRSD, Safety Factor)
Allometric scaling
( Conversion Based on Body surface Area)

4. From Decades of Research the Body Surface
is found to be Proportional to
Blood Volume
Amount of Plasma Protein
Oxygen Utilization
Renal Function
(In various Mammalian species..... )

5. Conversion Of Animal dose to Human Equivalent Dose Based on Body Surface Area
Species To Convert Animal
dose in mg/kg to
dose in mg /m2
Multiply by km
To Convert Animal Dose in mg/kg
Multiply Animal dose by Multiply Animal Dose
by
Human 37 ---- ----
Human Child(20kg) 25 ---- ----
Mouse 3 12.3 0.08
Hamster 5 7.4 0.13
Rat 6 6.2 0.16
Ferret 7 5.3 0.19
Guinea pig 8 4.6 0.22
Rabbit 12 3.1 0.32
Dog 20 1.8 0.54
Monkeys 12 3.1 0.32
Squirrel Monkey 7 5.3 0.19
Baboon 20 1.8 0.54
Micro Pig 27 1.4 0.73
Mini Pig 35 1.1 0.95

6. Animal Rights Activist
Testing efficacy of a Drug candidate in more than
one Animal Model
Dosing based on body surface area does not take
into account the process of drug elimination
New Discoveries ( Cellular and Organismic
Regulation and DNA )
“Animal Models are not very Predictive “?????

7. “Animal Models are not very Predictive “
Physiology between the two species
we understand little about normal and disease biology
Uncertainties due to enhanced sensitivity to Therapeutic
Activity
Difficulties in detecting certain toxicities
Unexpected toxicities
Inter Species differences in ADME of Therapeutic

8. Computer Based Modelling and
Stimulation
 Need to Develop a PK/PD Model
Physiological
Biochemical Process (Metabolising Enzyme)
 Age
Gender
Wish to get PK/PD studies done at Phase I to
reduce the risk subjected to healthy volunteers
In order to get more Efficacious Exposure Allometric
scaling results are compared

9. Pharmacokinetic/Pharmacodynamic
(PK/PD) Modelling
 The Imperial method of calculating the first in Human
dose may lead to the failure of many late stage clinical
trial
 Companies have moved to the PK/PD Modelling with
aim at predicting Dose Concentration Relationship
with safety and Efficacy.

10. Integrated Modelling of Biological
and Pathological Processes

11. Integrated Computer Modelling
HUMAN
Micro-dosing
• Pk &Pd
• MOA
• Specific Target
Bio-
Markers
• Signalling
Pathway
• e.g. Urinary
Protein
• Drug attrition
Animal
Studies

12. Developing a PK/PD Model
 To Incorporated Data from Previous
Animal Studies i.e..
What is Drug Target ?
 Agonist /Antagonist ?
Is There Intra cellular Signalling?
Are There Inhibition of Immunological Reaction?
Are There Off Target Effects?
Are There On Target adverse Effect?
Clearance And Bioavaibility
Drug Safety And Efficacy
Biomarker Response
Dose Range

14. Integrated Computer Modelling
Data used to
Programme
Computer
Stimulation
Biochemic
al Assay
Normal
Biology
Disease
Cellular
Regulation
Organismi
c
Regulation
Genomics
of Disease
Human
Genetics
Neurobiolo
gy
Non coding
DNA

15. Computer Modelling and Simulation is
Complementary to, but Cannot Replace,
Animal Studies
Pharmacokinetics
 Absorption
 Distribution
 Metabolism
 Excretion
 Pharmacodynamics
 Receptor Target
 MOA
 Post Receptor Effect (signal Transduction)
 Interaction of Drug with other Molecule

17. BENEFITS
Predictive models by easily incorporating proprietary
in-house data
 Identify potential safety risks much earlier in
discovery
Focus chemistry efforts on pre-clinical and clinical
safety
Rescue lost investment by Identifying a new
therapeutic application for a failed development
candidate
Helps to translate preclinical data into the design of
human clinical trials (Micro dosing).

19. PK/PD models Implemented in Pharmaceutical
Industry.
 Pfizer
 GlaxoSmithKline
 Lilly
 Novartis
 Entelos

20. Companies Providing Developed
Pk/Pd Models
Pharsight WinNonlin
(Phoenix WinNonlin Next Version Gastro Plus
Announced on June 2009.)................

21. Novartis has established a
dedicated M&S Department
Dr. Donald Stanski (former Vice President of
Scientific and Medical Affairs at Pharsight)
 Signal transduction Pathway and Safety Modelling
Economic Modelling and Decision Analysis
e.g.. Novartis Researcher successfully completed
the Modelling and Stimulation of Spinal Cord for T/t
of Injuries with Monoclonal Antibodies

22. Entelos focuses on building dynamic, large-scale
computer models of human physiology and
disease
In silico mechanistic models of human disease
Focuses on building dynamic, large scale computer models
Facing Difficulties in signalling pathway in the body
Virtual Patient Model
 Diabetes
 Obesity
 Immune/Inflammatory diseases( Asthma and Rheumatoid
arthritis)

23. Entelos/American Diabetes
Association virtual NOD mouse model
The design of a virtual non-obese diabetic (NOD)
mouse
 multiple genetic Determinants
 Components of the Immune System
 Beta-cell Physiology
 Pathobiology of type 1 diabetes

24. References
 EBook Modelling and simulation approaches in drug
discovery and development
Strategies for First to Man Studies.
 Pdf Adaptive Design workshop opportunities and challenges
• Pdf A dedicated SAS® Programming Group working in a
pharmaceutical Modelling & Simulation organization
 Pdf Novartis Accelerates Model Development Process
with Math Works Tools
 Ppt From Preclinical Data to Proof of Concept –