1. DRUG DISCOVERY AND DEVELOPMENT
DANJUMA N.M., PhD
DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS,
AHMADU BELLO UNIVERSITY ZARIA

2. Drug development is a dynamic activity with high interests at stake:
Availability of more effective or better tolerated treatments;
Therapeutic options for newer and emerging diseases;
Return on huge investments that are needed to discover and develop new drugs

3. Drug discovery process:
Development from herbal or traditional remedies – morphine (opium puppy, Papaver somniferum); atropine (deadly nightshade, Atropa belladonna);
Study of endogenous agents in animals – insulin, ancrod;
Serendipity – penicillin, clonidine, sulfonylureas, sulphasalazine

4. Ways of discovery…
Metabolites of existing drugs – paracetamol, oxazepam;
Empirical chemistry coupled with applied pharmacology;
Rational molecular design – β-blockers, histamine H2 antagonists;
Others – biotechnology, biosimilars

5. Toxicology:
Goal – not so much to find safe compounds and reject unsafe ones but rather to learn under which conditions a potentially beneficial compound can be harmful, and to find out how it can be used safely in humans if at all;
Performed in healthy animals – mice, rats, rabbit, dog, monkey etc..;

6. Toxicology… acute, sub-acute and chronic testing;
Route of administration is same as that of intended use in clinical studies

7. Acute toxicity studies:
Arithmetic method of Karber (1936);
Graphical calculation of Miller and Tainter (1944);
Graphical method of Lichtfeild and Wilcoxon;

8. Acute Toxicity Studies..
Arithmetic method of Muench and Reed;
Lorke method (1983);
Brine shrimp method;
OECD…..

9. Acute toxicity..
Maximal doses used should be (much) higher than doses subsequently used in humans;
Determines - 1) no-effect dose 2) threshold dose 3) maximal permissible dose 4) therapeutic index;
LD50 (TD50) is the index of acute toxicity (estimates risk of acute intoxication)

10. Lorke method:
Step 1: range of doses producing toxic effects is established e.g. 10, 100, 1000;
Step 2: based on results obtained, further specific doses are administered to calculate an LD50 ;
Assumptions: 1) substances more toxic than 1mg/kg are so highly toxic that it is not so important to calculate LD50 exactly 2) LD50 values greater than 5000 mg/kg are of no practical importance ;

11. Lorke method..
10(0/3) 100(0/3) 1000(0/3) – 1600(0/1) 2900(0/1) (1/1)

12. Sub-acute and chronic toxicity studies:
Repeated dose studies;
Determines adverse effects of the compound in the species tested and the target organ (behaviour, appearance, food intake, body weight, necropsy);
Whether the observed toxic findings are reversible and whether occurrence of toxicity will be easy to detect in clinical studies;
Results are extrapolated using AUC and Cmax

13. Duration of toxicity studies:
PERIOD OF CLINICAL USE
DURATION OF TOXICITY STUDY
Single admin. Or less than 1 week
2-4 weeks (14-28 days)
1-4 weeks, repeated
4-12 weeks (28-84 days)
1-6 months
3-6 months ( days)
Greater than 6 months
9-12 months ( days)

14. Screening procedures:
Study of pharmacology, pharmacokinetics and metabolism of the compound;
Simple screening;
Broad-based blind screening;
Programmed screening

15. Simple screening:
1 or 2 tests used to find substances with particular pharmacological properties e.g.;
The problem is to find a suitable, sufficiently accurate and inexpensive method;
Objective is to use suitable, sufficiently accurate method rather than a battery of tests;

16. Simple screening..
Test system selected are few and specific for a particular activity;
Very useful way to screen natural products with long traditional use in a particular diseases

17. Broad-based blind screening:
Detects pharmacological activity in a group of substances with no history of use;
Requires considerable planning and skilful execution of the tests, in order to economize time and fund;
Strategy employs simple and quick tests which should cover a broad area of biological activity;

18. Blind screening..
It requires knowledge of the established tests as well as ingenuity in their combination;
Useful when very little information is available on biological activity of new compound

19. Programmed screening:
Useful in the case of synthetic compounds when a specific type of drug is sought;
May also be used with natural products available in a fairly pure state;
Tests need greater precision.

20. Pharmacological tests:
Isolated tissue preparations or whole animals are used;
Standard agent to compare effectiveness;
Care must be taken in preparation of animal in order not to mask important effects;
Interpretation of results such as in rabbit ileum, guinea pig ileum, rat jejunum etc

21. CLINICAL TRIALS: Aims of the trial; Design of the trial;
Subjects to be studied;
Drugs to be tested;
Analysis and interpretation of results;
Ethical considerations.

22. Aim:
Compares effectiveness of a therapeutic strategy with another strategy or no therapy at all;
Assessment of benefit-risk ratio of the new compound;
Determination of the most appropriate dosage regimen

23. Basic design: Randomization; Blindness; Use of placebos;
Number of centres;
Methods of assesment;
Records.

24. Subjects: Numbers - Control subjects;
Criteria for selection or exclusion;
Disease characteristics;
In-patients or out-patients;
Age and sex;
Race;
Complicating diseases or drugs.

25. Drugs used: Dosage regimens; Run-in and wash-out periods;
Compliance – nature of treatment, xtics of patient, type of illness, behavior of doctor;
Other therapy – other drug a patient may take during trial

26. Analysis and interpretation:
Choice of statistical tests;
A priori hypothesis;
Intermittent analysis of data as they accrue;
Statistical versus clinical significance;
Extrapolation.

27. Ethics: Seeking informed consent of patients;
Use of placebo for comparison with a new treatment;
Improperly designed trials should not be carried out;
Control of ethical problems – ethics committee, insurers, law.

28. PHASES OF CLINICAL TRIALS:
Phase I
Phase II
Phase III
Phase IV (post marketing surveillance) etc..