Preclinical studies

Preclinical Studies in new drug development

1. Preclinical Studies Presented by : Ali Safdar Ehsan Elahi M. Ramzan Fayyaz Ahmed Aqeel Shahzad Mohsin Ali Azeem Imam MPHIL Pharmaceutics UCP Lahore

2. Preclinical studies are conducted to define pharmacological and toxicological effects not only prior to initiation of human studies but throughout clinical development. Both in vitro and in vivo studies can contribute to this characterization. Definition

3. Phases of Drug Development

4. Phases of Drug Development

5. Whether a drug will move on to studies in humans Designing phase I clinical trials . Help to identify criteria for evaluating safety in humans. Why Preclinical Testing?

6. Detect overt toxicity Identify, describe and characterize hazards - reversible? - clinically monitor able? Establish dose-response estimation of pharmacology and toxic effects Assess drug distribution to organ systems Identify metabolic, kinetic and elimination pathways Assess carcinogenicity, reproductive toxicity and teratogenic potential Why Preclinical Testing?

7. Medical uses/needs for substance Commercial potential Feasibility for mass production (manufacturing costs) Major considerations while doing Preclinical Studies

8. Short Term Animal Studies (Acute): Determine pharmacological action and toxicity Long Term Animal Studies (Chronic): Look for potential side effects that may result from long term use such as carcinogenicity Look for reproductive effects Types of Preclinical Testing

9. Data in two (2) Species is required Why 2 Species? Species differences in response Rodent – almost always rat Mouse has poorest clinical concordance Non-rodent – dog, non-human primate eg . Monkeys, apes Species Selection

10. Safety Pharmacology - functional assessment of major systems General Toxicology - target organs, “chronicity of the toxicity” Developmental and Reproductive Toxicology - fertility and reproductive performance - embryo/fetal development - neonatal development Overview of Study Types

11. Genetic Toxicology potential for cancer and heritable mutations Carcinogenicity 6 months, 2+ species, same route of administration to be used in humans) Teratogenic Studies Substance given to pregnant females and during lactation (usually rats & rabbits) Study Types Continu ……

12. Preclinical Studies continue along with Clinical Trials

13. Pharmacodynamics Pharmacokinetics Single dose toxicity in two species Repeated dose toxicity in two species, minimum 2 weeks. Local tolerance Teratogenicity study if fertile women are included in the study. Preclinical studies to be performed before phase I clinical trials

14. All genotoxicity studies Repeated dose toxicity. Duration depending on duration of clinical study Preclinical studies to be completed before phase II clinical studies.

15. Fertility studies Repeated dose toxicity In parallel with phase II and phase III clinical studies, other toxicity studies are completed Preclinical documentation before phase III clinical study

16. Steps involved with doing a Pre-Clinical Trial: File for approval as an Investigational New Drug (IND) 5 4 3 2 1 Establish Effective and Toxic Doses Screen the Drug in the Assay Develop a Bioassay Indentify a Drug Target

17. Step One: Get an idea for a drug target . Drugs target specific points in biochemical pathways Biochemical pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by chemical reactions. e.g. A B C D E Any step in the pathway, for example from A to B, or B to C, might be a target for the right drug.

18. A Bioassay is a “live” system that can be used to measure drug effect. It may be a culture of cells or organs or a whole animal. For example: Zebra-fish embryos - you can see effect of drugs on bone density, blood vessel growth and many other systems of the zebra-fish. Step Two: Develop a Bioassay

19. This is the actual test of the drug on the chosen bioassay. This will determine if the drug is SAFE and if it is EFFECTIVE in the bioassay (BEFORE it is ever tested on humans!) Step Three: Screen the drug in the Bioassay.

20. Establish what dosage amount of the drug is safe and what dosage amount of the drug is toxic . Most drugs have a toxic level or an amount at which the drug will become harmful instead of helpful. Step Four

21. Application is made to the Food and Drug Administration (FDA) as an Investigational New Drug (IND). IND must show how the drug: Is manufactured. Appears (color, solubility, melting point, particle size, moisture content). Formulated (pills, liquid, etc. + inactive ingredients). Will be analyzed for purity, concentration, stability. Will be tested for safety (this will be the basis for allowing first use in humans). Step Five

22. Get idea for drug target Develop a bioassay Screen chemical compounds in assay Establish effective and toxic amounts File for approval as an Investigational New Drug (IND) (leads to clinical trials) Review: Steps to New Drug Discovery Pre-Clinical Trials

23. Remington, the Science & Practice of Pharmacy, 21 st edition, Vol. 01, Pg. 965-972. Pharmaceutical Dosage Forms and drug delivery systems, 7 th edition by Howard C. Ansel http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405658.htm Reference

24. THANKS