W11: How Are Drugs Developed

Why are new drugs developed?

New drugs are made to have increased efficacy, and/or less side effects of current drugs

How are new drugs developed?

Long + expensive process (5-10yrs, and up to $1.5B), out of 1000s molecules made only 5-10 reach pre-clinical tests and of those only 1/20 go into clinical trials.

How are drugs discovered?

Observation and experience (natural)

Serendipity (chance)

Bioactivity screening (bioprospecting)

A targeted approach (rational drug design)

How does Observation and experience lead to the discovery of new drugs

Similarities

Connections or beliefs

Known activity 'tried and true'

How does Serendipity lead to the discovery of new drugs?

By luck, chance or an incorrect hypothesis: e.g. Viagra was made to decrease BP by gave blokes boners, penicillin

How does Bioprospecting lead to the discovery of new drugs?

Checking for bioactivity

- Checks for effect

- Dosage

- And general toxicity to normal cells

More and more pure bioactive compounds

- Identify structure and chemical purity

Main disadvantage is the complexity of this process

- Could be a rare resource from a rainforest

- May not be able to synthetically make it

What information does a rational drug design use to discover drugs?

A) To reduce cost of drug screening

B) Injected human antibodies coat tumour cells and make immune system response quickly to them

1. Find useful antibody = mABs enhances body's own immune system

e.g. Complement lysis due to complement binding site on antibody, antibody dependant cell-mediated cytotoxicity (ADCC) where any cells coated in mABs are killed by NK cells

2. Disease process = identify biochemical pathway

3. Mode of action = effect

4. Structure of critical molecules = Structures

5. Latest trend - pharmacogenomics "individualised medicine" = inheritance

6. Choose a target = Computer screening methods

7. Optimising leads = More QSAR modelling

What percentage are human mABs Chimeric, Humanized and Fully human Abs?

Chimeric=66%

Humanised= 90%

Fully human= 100% -- very few created.

Single dose Toxicity Studies (Acute)

Effects observed (usually in rats and

mice) after a single dose i.e. mortality, clinical signs (lethargy, body weight changes, etc.)

• Investigation of possible target organs by full autopsy

Repeat-dose toxicity studies

Sub-acute (14 day), sub-chronic (3-6 months) &

chronic (1-2 yrs) studies (usually oral dosage used for longer exposures)

• In 2 relevant species, both genders

• To determine target organs and dosage protocols for

chronic studies

Measurements:

• food/water consumption, body weights

• any other observed abnormalities (e.g. neuronal)

• full autopsy and clinical chemistry on blood haematology & urinalysis

• major tissues examined histologically

What is the purpose of Genotoxicity studies?

To identify any DNA damage.

What is the weight of evidence when it comes to genotoxic studies?

Eukaryote>prokaryote

In vivo> in vitro

Germ> somatic cell

What is the cell system used in Genotoxic studies which identifies gene mutations? And what is the test?

• In vitro non-mammalian cell system - e.g. gene

mutation assays (Ames Test)

• In vitro mammalian cell system - e.g. chromosomal

& DNA damage (unscheduled DNA Synthesis)

• In vivo mammalian system - e.g. chromosomal

damage (clastogenic) assays & other genotoxic effects

• Other systems

What do carcinogenicity studies test?

A long-term study which tests for chronic toxicity. Measurements of food/water consumption, weight changes, and full autopsy and clinical chem taken at 0.5, 1, and 2year marks.

The Type and incidence of tumours recorded. The incidence must be higher that that of spontaneous tumours to be of importance.

What are the dosages in a carcinogenicity study?

High dose at MTD (10% body weight) or at 100x recommended human dose. , A medium dose.

Or a low dose at NEL (below the effective level)

What do Phase 1 clinical trials include?

Is it safe?

24 - 30 months

A small no. of normal volunteers given a single dose at 1/20 or 1/30 LED (lowest effective dose). The dosage is increased until effects are seen, the nature, duration and severity of effect is noted.

What do Phase 2 clinical trials include?

Does it work?

12 - 24 months

EARLY: small no. of select patients (have disease) used to authenticate efficacy and approximate dose range.

LATE: large no. of select patients used over a longer time period to find final dose range and form data on elimination and metabolism.

What do Phase 3 clinical trials include?

Is it better than the standard treatment?

12 - 24 Months

Large no. of select patients used to find responsiveness as well as identify any less common AE.

Drug may be compared to placebo or reference drug of known efficacy. Drug interactions may also be investigated.

What do Phase 4 clinical trials include?

Conditional approval

12 - 36 months

MONITERED RELEASE: Patients are supervised by hospitals/doctors to monitor drug efficacy and AE under limited marketing.

POST MARKETING SURVEILLANCE is then done where the Pt is monitored in the conditions of actual drug use to identify any patterns of use and any additional efficacy and toxicity post-marketing.

Who supervises phase 1&2 clinical trials?

Clinical pharmacologists.

Who supervises phase 3 clinical trials?

Clinical investigators.

Who dupervises phase 4 clinical trials?

Medical physicians.

What is the difference between a "between-subjects" and a "within-subjects" study design?

Between-subjects design involves one treatment per patient, while within-subjects design gives each patient more than one treatment serially.

In a blind study, who is unaware of which medication is being administered?

The patient.

In a double-blind trial, who is unaware of the treatment allocation?

Both the patient and the physician.

What study design is best for controlling the placebo effect?

Crossover study design:

Two randomised groups of patients each receive either a placebo or the reference drug, then switch

What does ACM mean regarding the TGA?

Advisory Committee on Medicines: Responsible for evaluating and allowing certain drugs for prescription-only, non-prescription, and over the counter (OTC) medication.

What does ARTG mean regarding the TGA?

Australian Register of Therapeutic Goods: a list of approved drugs, as well as what labelling and info needs to be listed.

What does SUSMP mean regarding the TGA?

Standard for Uniform Scheduling of Medicines & Poisons

What does PBS mean regarding the TGA?

Pharmaceutical Benefits Scheme: a scheme to lower the cost of vital drugs for those who need them.

What does Aust L mean regarding the TGA?

A drug listed for Quality and Safety only. NOT Efficacy.

Health claims are low level

What does Aust R mean regarding the TGA?

A drug listed for Quality, Safety, AND Efficacy.

Health claims are high level