MP3. Drug development (pre clinical)

Question 1

Purposes of preclinical development?

Answer 1

-transform a drug into a medicine
-prove drug candidate is safe and effective before trials in humans
-collects scientific data to prepare IND application
ONE NOTE

Question 2

Aspects of pre-clinical development?

Answer 2

-Chemical process development
-Development of delivery method(s)
-Further in vitro ADMET testing
-Animal studies
(Pharmacokinetics, toxicity, efficacy and dosing)
-IND* application

Question 3

purpose of chemical process development?

Answer 3

-optimisation of chemical synthesis
-scale up synthesis from lab to industrial scale
-development of analytical methods
ONE NOTE

Question 4

Purpose of development of delivery methods?

Answer 4

formulate the drug candidate into a suitable ‘vehicle’ for:
-clinical trial (simple formulation (liquid, capsules)
-Commercialisation (usually, more complex product (ex: tablets), Will be optimised after first clinical trials, Oral administration always preferred)

Question 5

What are the stages in the development of delivery methods?

Answer 5

1)pre-formulation
2)formulation
3)stability testing

Question 6

Describe the pre-formulation stage

Answer 6

Understanding the chemical, physical and mechanical properties of the drug candidate:
-Crystal/salt forms
-Solubility profile
-Particle size, shape, hygroscopicity
-Powder flow properties
-Stability in solution, in a dry form, at high temperatures
-Compatibility with excipients

Question 7

Describe formulation stage

Answer 7

Design of the ‘vehicle’ for clinical trials, then of the medicine
-Choice of dosage form, excipients, etc…

Question 8

Describe stability testing stage

Answer 8

-At different temperatures, humidity levels, light conditions
-In different packaging

Question 9

Purpose of in vitro ADMET testing?

Answer 9

-Absorption: What are the mechanisms of drug transport across the intestine? Are membrane transporters involved?
-Distribution: Which membrane transporters does the drug candidate interact with?
-Metabolism: Which metabolising enzymes (Cytochrome P450) are involved? Are the metabolites active/toxic? How do they leave liver cells?
-Excretion: What are the mechanisms of drug/metabolite elimination through the kidneys?
-Toxicity: Any risks of chronic effects (ex: inflammation)?

Question 10

importance of ADMET testing?

Answer 10

ADMET process can be affected by:
-Other drugs, food, herbal remedies (drug-drug or drug-food interactions)
-Gender, age, ethnicity, pregnancy, diseases, etc…
-Genetic variations (mutations)
-Risk of serious adverse effects or lack of efficacy in certain individuals (ex: codeine)
-ADMET in vitro data must be provided as part of the IND applicatio

Question 11

advantages of in vitro testing?

Answer 11

-HTS possible
-cost effective
-more ethical
-human models available
-mechanisms can be studied

Question 12

Limitations of in vitro testing

Answer 12

-simplified models
-models often different tissue in vivo (cell lines)
-no interconnections between different biological systems

Question 13

Describe animal studies stage?

Answer 13

-Only on the most promising drug candidates based on in vitro testing
-Different species used
-Rodents (rats, mice, guinea pigs)
-Non-rodents (rabbits, dogs, mini pigs)
-Monkeys (very rarely)
-Tightly regulated (under GLP =
Good Laboratory Practices)

Question 14

What is tested in animal testing?

Answer 14

-pharmacokinetics profile
-toxicity
-efficacy and dosing

Question 15

Describe how the pharmacokinetics profile is studied in animal testing?

Answer 15

-In rats first; then larger species
-Small number of animals (2/3 per drug candidates)
-Drug administered by the intended route
-Blood (and urine) samples taken
at regular time intervals
-Are the rates of absorption and
elimination appropriate for the
intended disease?

Question 16

Describe how toxicity is tested in animal studies

Answer 16

-In two species (rodent + non-rodent)
Different stages
-Acute toxicity: ascending single doses
-Chronic toxicity: repeating dosing over 3-14 weeks or 6-12 months if chronic condition to be treated
-Carcinogenicity & teratogenicity: repeating dosing over 12-24 months

-Determination of Maximum Tolerable Dose:
Must be significantly higher than minimum effective dose (drug is abandoned otherwise)

Question 17

Describe how efficacy and dosing is tested during animal studies

Answer 17

-In the most appropriate species (ex: guinea pigs for asthma)
-In an animal model of the human diseases,
Issue: animals generally do not develop human diseases
-Determination of the range of doses that is effective without causing adverse effects
-Many drug candidates fail to show efficacy (poor in vitro/in vivo correlation)

Question 18

Describe IND application stage

Answer 18

-Approval required from Government Agencies before first tests in humans
-Also called ‘Clinical Trial Authorisation’ (CTA)
-Incredibly long document to be submitted proving the new drug is safe and effective
ONE NOTE

Question 19

What government agencies need approval before testing in humans in IND application?

Answer 19

-Food and Drug Administration (FDA, USA)
-European Medicine Agency (EMA, EU)
-Medicine and Healthcare products Regulatory Agency (MHRA, UK)
-Pharmaceuticals and Medical Agency (PMA, Japan)