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Moving from animal model to the clinic
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.
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
13.
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
16.
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).
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 –