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Moving from animal model to the clinic


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Moving from animal model to the clinic

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 10. Integrated Modelling of Biological and Pathological Processes
  11. 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. 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. 13. 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
  14. 14. 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
  15. 15. 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).
  16. 16. PK/PD models Implemented in Pharmaceutical Industry.  Pfizer  GlaxoSmithKline  Lilly  Novartis  Entelos
  17. 17. Companies Providing Developed Pk/Pd Models Pharsight WinNonlin (Phoenix WinNonlin Next Version Gastro Plus Announced on June 2009.)................
  18. 18. 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
  19. 19. 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)
  20. 20. 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
  21. 21. 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 –