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Pharmacology > Drug discovery > Flashcards

Drug discovery Flashcards

1
Q

give examples of where drug discovery and release has gone wrong:

A
  1. elixir sulfanilamide - contained diethylene glycol which killed 107 people
    2 sulfathiazole tablets - had sedative phenobarbital in it which caused 300 deaths
  2. thalidomide - sleeping pill which caused severe birth defect of arms and legs in 10000-20000 babies
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2
Q

what are the phases of drug discovery?

A
  1. target selection
  2. preclinical research - animal testing
  3. clinical research:
    - phase 1 = tests on healthy humans
    - phase 2 = patient entry
    - phase 3 = proving to regulatory authorities e.g. FDA
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3
Q

what is target selection?

A
  1. functional proteins identified from bioscience research
  2. lead finding: automated screens against libraries
    - when the biochemical target has been identified, the lead compounds must be identified
    - cloning of human target protein is used and an assay is developed to measure the functional activity of the target protein
    - predict toxicology
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4
Q

how are animals used in preclinical research?

A

rodents (rat) and non-rodents (beagles) are given 3 dose groups:
- low = no toxicology
- intermediate = reversible toxicology
- high = toxicology expected to be seen in target organ

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5
Q

what is clinical pathology vs pathology?

A

clinical pathology: haematology/clinical chemistry (lab results)

pathology: large organ toxicity

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6
Q

what are the goals of non-clinical safety evaluations?

A

toxicity:
- on-target = drug goes to wanted target,
- off-target = drug causes unwanted side effects

toxicokinetics: relate toxicity to exposure
- increase in dose should cause linear increase in toxicity effects
- preliminary toxicological testing to eliminate genotoxicity

identify max non-toxic dose/minimum effective dose

pharmacokinetic testing (ADME)

feasibility of large scale synthesis and purification

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7
Q

what is safety pharmacology?

A

the investigation of potential undesirable effects of drugs on physiological functions:
- test CVS (in vitro and in vivo)
- test CNS (rodent tests)
- test respiratory system (rodent tests)

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8
Q

what preclinical conclusions must be made before starting clinical human trials?

A
  • evidence of pharmacological activity
  • maximum non-toxic dose
  • identify possible adverse effects on target organs
  • show relationship of effects to dose and exposure
  • differences observed in different species
  • evaluation of risk in humans
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9
Q

what is phase 1 of clinical trials?

A

IS IT SAFE?
- referred to as First in Man
- aim: test the drug is safe in humans and check for dangerous effects on CVS, respiratory, hepatic or renal functions
- test tolerability - does the drug produce unpleasant symptoms such as nausea?
- test pharmacokinetic properties - is the drug well absorbed? what is the time course of the plasma concentration?

performed on a group of 20-80 healthy volunteers - first cohort receives low dosage which is then adjusted for the following cohort

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10
Q

what is an example of phase 1 trials going wrong?

A

BIA 10-2474:
- fatty acid hydrolase inhibitor to treat anxiety disorder of Parkinson’s and for chronic pain of MS, cancer, hypertension and obesity
- interacts with endocannabinoid system
- phase 1 trials led to serious adverse effects in 5 participants - 1 person died after having 50mg repeat dose due to lack of metabolism of the drug in the brain
- 1.25mg would have been enough for saturation, which should have been identified in preclinical trials

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11
Q

what is phase 2 of clinical trials?

A

PROOF OF CONCEPT - how much should be given to be effective?
- performed on 100-300 patients to test for efficacy in clinical situations and establish dosage
- covers several clinical disorders such as anaemia and rheumatoid arthritis to identify therapeutic indications for the new compound and dose needed

made up of phase 2a and phase 2b

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12
Q

what is phase 2a of clinical trials?

A

conducted in healthy volunteers or patients to determine pharmacodynamics and biological activity:
- proof of efficacy
- studies on the mechanism of action of the drug
- exploring a range of doses
- pilot studies

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13
Q

what is phase 2b of clinical trials?

A

definitively finding the dose range and efficacy in patients:
- used as pivotal trials if the drug is intended to treat life-threatening or severely debilitating illnesses
- definite dose finding studies

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14
Q

what is phase 3 of clinical trials?

A
  • over 1000 patients
  • need definitive results via: double-blind, randomised trials
  • compare new drug with commonly used alternatives
  • multinational trials
  • application for marketing is made

includes phase 3a and 3b

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15
Q

what is phase 3a in clinical trials?

A
  • study designed to get statistically significant evidence of efficacy and safety for NDAs approval
  • pivotal studies: provide evidence for a drug marketing approval via randomised, double-blind, placebo trials
  • long-term safety studies for registration
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16
Q

what is phase 3b in clinical trials?

A

study started prior to approval with intention to support publications, claims or to prepare launch
- not intended for regulatory submissions

17
Q

what is phase 4 in clinical trials?

A
  • post marketing surveillance to detect rare or long-term adverse effects from the use of the drugs in a clinical setting with thousands of patients
  • can lead to limitation of drug use by certain patients, or even complete withdrawal of the drug
18
Q

what are some drugs which have been withdrawn from the market?

A
  1. sibutramine (appetite suppressant) - heart attack and stroke
  2. propoxyphene (opioid painkiller) - heart attack and stroke
  3. drotrecogin alpha (severe sepsis) - had no benefit
  4. rimonabant (obesity) - severe depression and suicide
  5. hydromorphone (narcotic painkiller) - high risk of accidental overdose with alcohol
19
Q

what is a small molecule drug?

A
  • low molecular weight
  • chemically synthesised
  • well-defined structure
  • not complex
20
Q

what is a biological molecule drug?

A
  • high molecular weight
  • derived from living organisms
  • large and complex structure
21
Q

what is a monoclonal antibody?

A
  • high molecular weight
  • derived from living organisms
  • complex
22
Q

what are biologics?

A
  • drugs which are derived from living organisms
23
Q

how have biologics contributed to new medicines?

A
  1. antibody-based: anti-VEGF
  2. vaccines: HPV-vaccine, COVID19-vaccine
  3. RNAi: Duchenne Muscular Dystrophy
  4. cell-based: CAR-T for children with acute lymphoblastic leukaemia
  5. gene therapy: adeno-associated virus causes haemophilia
    - plasmid is delivered to body so the body can produce its own clotting factor 9 enzyme
24
Q

what are biopharmaceuticals?

A

products in which the active substance is produced by, or extracted from, a biological source e.g. monoclonal antibodies to be a human protein
- off-target toxicology is rare

25
Q

what are the adverse reactions of biopharmaceuticals?

A
  • exaggerated pharmacology
  • anti-drug antibody responses - immune system fighting the biologic, causing accelerated clearance and metabolism to neutralise the pharmacological activity
  • on-target toxicity can be high - target can be hit so strongly that it causes adverse effects, so balance is critical
  • max dose: 10x max exposure in clinic
26
Q

what is the immunotoxicity of small molecule drugs and biopharmaceuticals?

A

small molecule: often unexpected, off-target reactions

biopharmaceuticals: cytokine storms

27
Q

what is the phase 1 dose?

A

minimum effective dose:
smallest possible dose that will bring about a response from the organism
- minimum anticipated biological effect

28
Q

what is CD28-superMAB (TGN1412)? what happened during its clinical trials?

A
  • immunomodulatory drug which was withdrawn from development after inducing severe inflammatory reactions in phase 1 trials
  • was intended to treat B cell chronic lymphocytic anaemia
  • strong agonist for CD28 receptors on T cells
  • preclinical profile was good - showed doses with no side effects
  • in phase 1, 6 volunteers went into possible as they developed fever
  • the drug caused a cytokine release syndrome (like an anaphylatic shock)
29
Q

what is immunotherapy?

A
  • form of cancer treatment that uses the immune system to attach cancer cells
30
Q

what are checkpoint inhibitors in immunotherapy?

A
  • causing a natural break in the immune system so that the immunity T cells recognise and attack tumours
31
Q

what is CAR-T cell therapy?

A
  • chimeric antigen receptor (CAR) T cell therapy is the genetic engineering of a patient’s own immune cells to make new protein to fight tumour cells
  • T cells are taken from a patient and their receptors are altered to recognise tumours
32
Q

how was CAR-T cell therapy developed?

A

1990 - cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) was found on T cell surface which could be blocked, leading to tumours vanishing

1999 - checkpoint inhibitors:
- programmed cell death protein 1 (PD1) on T cell dampens down the immune system
- programmed death-ligand 1 (PD-L1) protects cancers from T cells
- these proteins were how cancer evaded the immune system, so if these receptors are blocked, the immune system can detect and destroy the cancer

33
Q

what was the action of the anti-CTLA-4 antibody?

A
  • worked against the CTLA-4 receptor on T cells to treat malignant melanoma
  • CTLA-4 on T cells bind to B7 proteins which in turn prevent the T cells from activating and attacking tumour cells
  • the anti-CTLA-4 antibody blocks CTLA-4, so T cells can activate and attack cancer cells
34
Q

what is the major histocompatibility complex?

A

MHC is a set of cell surface proteins essential for the acquired immune system to recognise foreign molecules
- they bind to antigens derived from pathogens and display them on their surface for T cells to recognise

35
Q

what is pembrolizumab?

A
  • a drug which blocks PD-L1 to treat lung cancer
  • can eliminate, regress or stabilise cancer, with long lasting effects
  • only works on cancers with PD-L1 receptor
36
Q

how are chimeric antigen receptors made for CAR-T therapy?

A
  • CARs are produced by splicing together the gene for an antibody that recognises a tumour antigen, and the gene for a receptor that sits on surface of T cells
  • this new gene is inserted into the T cell, causing it to target the tumour
37
Q

What is the process in which CD3 cells are made to target cancers? (example of CAR-T)

A
  • CD3 cells with CD19 marker are extracted and modified with a plasmid (transfection)
  • cells are formulated into a new therapy and monoclonal antibody fuses with the receptor on T cells to attack cancers
  • cells are put back into the patient without rejection and destroy the cancer
38
Q

what are the limitations of CAR-T therapy for CD19 blood cancers?

A

CD19 is only common to the surface of a few blood cancers

can cause fatal immune reactions:
- cytokine-release syndrome
-B cell aplasia
- brain swelling
- neurotoxicities

Pharmacology (10 decks)

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