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BMS 242 - Core Phys/pharm > Drug development > Flashcards

Drug development Flashcards

1
Q

What are the 5 stages of developing a new drug?

A

1) Basic research to target selection
2) Pre-clinical research
3) Clinical development
4) Regulatory review
5) Postmarketing surveillance

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2
Q

What does basic research to target selection lead to?

A

The identification of a target through basic understanding of the disease

Eg. it is known that inhibiting a certain receptor has a certain effect - makes sense to look for antagonists of this receptor

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3
Q

What occurs in pre-clinical research?

A

Evaluation of drugs in animal models

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4
Q

What occurs in clinical development?

A

3 phase testing of the drugs in human patients

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5
Q

What are the most common drug targets?

A

Enzymes
Receptors
Transport proteins

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6
Q

How is a lead target found?

A

Use the lead target to find the lead compound:

  • Clone the lead target
  • Using an assay, test many compounds, to test the functional activity of the target (eg. enzymatic activity if the lead target is an enzyme)
  • Normally use AUTOMATED screens, which test all the compounds in a chemical library
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7
Q

What is a chemical library?

Why are they used in lead compound selection?

A

A library of molecules created by combinatorial chemistry:
- Creating MANY compounds which are all related to a ‘parent’ compound

Used in lead compound selection as the different compounds have slightly different shapes/properties

Therefore one may fit better into the lead target

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8
Q

What process is done after the lead compound is selected?

A

LEAD OPTIMISATION

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9
Q

What is the need for lead optimisation?

A

1) Improve target specificity (reduced side effects?)
2) Improve potency

3) Improve pharmaceutical and pharmocokinetic problems
(look at potential problems of what the drug may metabolise into)

4) Reduce safety liabilities

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10
Q

What do the steps in pre-clinical development aim to test?

A

1) Genotoxicity
2) Regulatory safety evaluations
3) Non-clinical safety evaluations
4) Pharmacokinetics
5) General toxicology and animal toxicology

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11
Q

What is genotoxicity?

A

Testing the destructive effects of the drug on the cells genetic material

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12
Q

What is tested when testing the regulatory safety of a drug?

A

If the drug has any obvious behavioural effects and effects on the:

1) Respiratory system
2) CV system
3) CNS

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13
Q

Why can the same prediction methods not be used for small molecules and biomolecules?

A
  • Biomolecules have different properties to small molecules
  • Many post-translational modifications occur on biomolecules when they are synthesised and this can impact how they are handled in the body
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14
Q

What do biomolecules break-down into?

Why is this advantageous?

A

Amino acids by proteases

No toxic metabolites

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15
Q

Which takes longer to test: small molecule drugs or biomolecules?

Why?

A

Small molecules:

  • Must test carcinogenicity, genotoxicity etc (doesn’t already exist in the body)
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16
Q

What are the goals of non-clinical safety evaluations?

A

1) Time duration of the drug

2) Metabolic affects
(May produce inactive version - stay around for longer)

3) Toxicity
(Reversibility, on/off target)

4) Toxicokinetic
(toxicity to exposure)

5) Max non-toxic dose/ min affective dose
6) Dose selection for first in humans
7) Identification of specific monitoring requirements

17
Q

What is the general toxicology testing?

A

Pathology:

Haematology
Changes in immune system
Kidney/liver function
Coagulation

Large organ toxicology

18
Q

Describe animal toxicology testing, when relating to SMALL MOLECULES?

A
  • Use rodents and non-rodents (beagle)

Three dose groups tested:

  • Low (non-toxic)
  • Intermediate
  • High (toxicology expected in target organ)
19
Q

What are the differences between small molecules and biopharmaceuticals?

A

Biopharmaceuticals:
- Proteins from the body which are enhanced and used as drugs

Small molecule drugs:
- Synthetic (man-made) drugs which MIMICK the effect of endogenous compounds OR from biological PLANT material

20
Q

Is off-target toxicology common in biopharmaceuticals?

Why?

A

No

They are broken down into NON-TOXIC amino acids
They do not enter cells

21
Q

What animal models are used for testing biopharmaceuticals?

A

Non-human primates

22
Q

What are the adverse reactions that can be caused by biopharmaceuticals? Describe them (2)

A

1) Exaggerated pharmacology
- May have higher specificity than expected
- Therefore, stronger reaction

2) Anti-drug antibody reaction
- May have accelerated clearance
- May have prolongation of exposure
- May neutralise the pharmacological activity

23
Q

With which type of drug is there often rare and unexpected off-target?

A

Small molecule

24
Q

What are the immunotoxicology risks of small molecule drugs?

A

1) Haematological change
2) Weight change
3) Infection of spleen, lymph node (histopathy - changes in tissues do to disease)

25
Q

What are the immunotoxicology risks of biopharmaceutical drugs?

A

1) Infusion reaction (fever, chills etc)
2) Cytokine storm (organ failure)
3) Immunosupression (leave animal vunerable to other diseased)
4) Autoimmunity

26
Q

What must be concluded before testing drugs in humans?

A
  • Evidence of activity
  • Maximum non-toxic dose
  • Adverse effects on target organs
  • Relationship of effects to dose and exposure
  • Differences observed in different species
  • Evaluation of risk in humans
27
Q

When testing drugs on humans, what dose are they tested with?

A

Dilutions LESS than the lowest dose tested in animals

28
Q

Who is tested in phase I of clinical trials?

A

Small number of HEALTHY volunteers (20-50)

29
Q

What are the questions answered in phase I of clinical trials?

A

1) Is the drug safe
2) Is the drug well tolerated (nausea, vomiting, headache etc)

3) What are the pharmacokinetic properties?
(fully accountable throughout body, exert all response)

30
Q

Who and how is tested in phase II of clinical trials?

A

NOT blind test on more volunteers (100-500) who HAVE the disease

31
Q

What are the questions answered in phase II of clinical trials?

A

1) How much should be given to be effective?

2) How well does the treatment work?

32
Q

Who and how is tested in phase III of clinical trials?

A

Randomised DOUBLE BLIND tests on 1,000-5,000 volunteers:

  • Multi-centre (different hospitals)
  • Multi-national
  • Patients with OTHER conditions
33
Q

What might phase III of clinical trials show?

A

Individual variance

34
Q

What happens in the regulatory approval stage?

A
  • Look at ALL of the data
  • Scrutinised by regulatory agencies all over the world, who don’t work together (drug may be accepted by one but not another)
  • Look at value for money
35
Q

When testing biomolecules, in the pre-clinical stage, what must be looked at?

A

Pharmacokinetics (broken down into amino acids)

Immunogenicity (rejection)

BMS 242 - Core Phys/pharm (13 decks)

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