Preclinical studies are conducted before human trials to assess pharmacological and toxicological effects. Both in vitro and in vivo studies characterize these effects. Preclinical testing aims to detect toxicity, understand hazards, establish dose responses, and assess distribution, metabolism, and carcinogenicity. It involves short and long term animal studies in two species, as well as safety pharmacology, toxicology, developmental and reproductive toxicity testing, and genetic and carcinogenicity studies. The steps of preclinical trials include identifying a drug target, developing a bioassay, screening compounds, establishing effective and toxic doses, and filing for investigational new drug approval.

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, 21st
edition, Vol. 01, Pg. 965-972.
 Pharmaceutical Dosage Forms and drug delivery
systems, 7th edition by Howard C. Ansel
 http://www.fda.gov/ForPatients/Approvals/Drugs/uc
m405658.htm
Reference

25. THANKS