Moving from Animal Model to the Clinic

Dr. Govind GiraseUDIRT, MUHS 1st Year 2012.

Saturday Club

“A Complimentary Market Research Study”

Author: Insight Pharma Reports

Publisher : Cambridge Healthtech Institute

USE OF EXTENSIVE TECHNOLOGIES IN PHARMACEUTICAL RESEARCH

To improve operational efficacy of Drug Development

Economical pressure in drug development

To Save Drug development Time

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)

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..... )

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/kgMultiply Animal dose by

Multiply Animal Dose by

Human 37 ---- ----Human Child(20kg)

25 ---- ----

Mouse 3 12.3 0.08Hamster 5 7.4 0.13Rat 6 6.2 0.16Ferret 7 5.3 0.19Guinea pig 8 4.6 0.22Rabbit 12 3.1 0.32Dog 20 1.8 0.54Monkeys 12 3.1 0.32Squirrel Monkey 7 5.3 0.19Baboon 20 1.8 0.54Micro Pig 27 1.4 0.73Mini Pig 35 1.1 0.95

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 “?????

“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

Computer Based Modelling and Stimulation Need to Develop a PK/PD Model

Physiological Biochemical Process (Metabolising Enzyme) AgeGender

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

Pharmacokinetic/Pharmacodynamic (PK/PD) ModellingThe 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.

Integrated Modelling of Biological and Pathological Processes

Integrated Computer Modelling

HUMAN Micro-dosing

• Pk &Pd• MOA• Specific

Target

Bio-Marke

rs• Signalling Pathway

• e.g. Urinary Protein

• Drug attrition

Animal Studie

s

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 BioavaibilityDrug Safety And Efficacy Biomarker ResponseDose Range

Integrated Computer Modelling

Data used to Programme Computer

Stimulation

Biochemical Assay

Normal Biology

Disease

Cellular Regulation

Organismic Regulation

Genomics of Disease

Human Genetics

Neurobiology

Non coding DNA

Computer Modelling and Simulation is Complementary to, but Cannot Replace,Animal StudiesPharmacokinetics

Absorption Distribution Metabolism Excretion

Pharmacodynamics Receptor Target MOA Post Receptor Effect (signal Transduction) Interaction of Drug with other Molecule

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

safetyRescue 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).

PK/PD models Implemented in PharmaceuticalIndustry. Pfizer

GlaxoSmithKline

Lilly

Novartis

Entelos

Companies Providing Developed Pk/Pd ModelsPharsight WinNonlin

(Phoenix WinNonlin Next Version Gastro Plus Announced on June 2009.)................

Novartis has established a dedicated M&S DepartmentDr. 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

Entelos focuses on building dynamic, large-scalecomputer models of human physiology and

diseaseIn 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)

Entelos/American Diabetes Association virtual NOD mouse modelThe 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

References EBook Modelling and simulation approaches in drug

discovery and developmentStrategies 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 –