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

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

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

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

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..;

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

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

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

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)

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 ;

Lorke method.. 10(0/3) 100(0/3) 1000(0/3) – 1600(0/1) 2900(0/1) 5000 (1/1)

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

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 (90-180 days) Greater than 6 months 9-12 months (270-365 days)

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

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;

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

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;

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

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.

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

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.

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

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

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

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

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

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.

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