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DRT and synoptic exam revision > Drug development > Flashcards

Drug development Flashcards

1
Q

How long does drug discovery and development usually take?

A

10-20 years

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2
Q

What are the steps in drug development?

A

Phase 1= healthy patients

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3
Q

Why was 11-beta-HSD1 used a therapeutic target in AD disease?

A

11-beta-HSD1 regulates cortisol
It converts inactive cortisone to active cortisol in the brain, liver and fatty tissue
There is evidence that memory loss and depression are linked to high cortisol
Reduce cortisol= may affect memory

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4
Q

What evidence is there that high cortisol may affect memory and AD disease?

A

High brain cortisol linked to memory loss and depression
Lupien et al 1998 found that hippocampal volume and memory correlate with cortisol levels
If mice are treated with glucocorticoid, there is more memory loss
Glucocorticoids increase amyloid-eta and tau pathology in a mouse model of AD disease

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5
Q

What is the HPA axis diagram?

A

Adrenocorticotropic hormone (ACTH)
Corticotrophin releasing hormone

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6
Q

Why does the drug created to block 11B-HSD1 need to be highly specific?

A

Blocking HSD2 would cause a rise in blood pressure

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7
Q

What is a key symptom of Cushing’s disease and why does that affect AD?

A

Cushings= high cortisol usually due a tumour of the HPA axis
Key symptom is memory loss
Therefore high cortisol is linked to memory loss- reducing cortisol levels may help with AD.

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8
Q

What evidence was there that blocking 11B-HSD1 would help with AD disease?

A

11B-HSD1 -/- mice resist cognitive decline with aging
Aged mice fail in the watermaze compared with young mice. If you block HSD11B1 they do not get cognitive decline and act like young mice
Furthermore, pharmacological inhibition by CBX (non selective HSD1 inhibitor) in humans improves cognition and certain aspects of memory

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9
Q

How were the effects of a 11B-HSD1 inhibitor measured?

A
  • Need to be able to measure effects of the drug using biomarkers such as ACTH, adrenal androgens or urinary metabolites such as THF
  • Cannot measure cortisol as HPA axis adjusts for the loss of cortisol
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10
Q

What is important to consider when creating a drug that targets hormones?

A

May cause an increase/ decrease in other hormones
May be a problem for pre-menopausal women

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11
Q

What does a drug need to be in order to be successful?

A

It needs to be not too polar or not too lipophilic
There also needs to be accessible pockets that are druggible

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12
Q

What technique is SPA?

A

Scintillation proximity assay
In a typical SPA, small beads (usually made of yttrium silicate or polystyrene) are coated with a material that can bind to the biomolecule of interest. For instance, if you’re studying a protein-protein interaction, one of the proteins might be immobilized onto the surface of the beads.
Radiolabeling: The biomolecule to be detected is often radiolabeled, usually with a radioactive isotope such as ^3H or ^125I. This can be done by incorporating the radioactive label during synthesis or by chemically modifying the molecule after synthesis.
Proximity Detection: When the radiolabeled biomolecule comes into close proximity to the surface of the bead (usually within a few nanometers), it emits radiation, typically beta particles.
Scintillation Detection: The emitted radiation interacts with a scintillant material, which converts the energy of the radiation into photons of light. This light emission is then detected by a photomultiplier tube or other light-sensitive detector.
Measurement: The amount of light detected is proportional to the amount of radiolabeled biomolecule bound to the beads, which in turn reflects the concentration of the biomolecule in the sample.

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13
Q

What is the HTFR technique?

A
  • HTFR= Homogeneous Time-Resolved Fluorescence. The interacting molecules are labeled with two different fluorphores (one acts as donor and one acceptor).
  • When the donor fluorophore is excited with a specific wavelength of light, it transfers its energy to the acceptor fluorophore if they are in close proximity, and this causes emmission of flurescence
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14
Q

What are the main ways new drugs can be discovered?

A

Modify current ligands- from patents, current drugs
X ray to discover the structure and use models to work out a structure that will fit
High throughput screening- screen millions of compounds using robotics
Fragment screening- screening small low-molecular-weight compounds to identify initial hits that can be further developed into compounds
In-silico screening- use computational methods and simulations that predict binding strength of ligands. AI increasingly being used

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15
Q

What techniques did researchers on the 11B-HSD1 inhibitor project use for drug discovery?

A

A combination of modifying patents and in silico screening

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16
Q

What is important to include in a target product profile when designing a drug?

A

Efficacy
Site of action
Clinical indication
Route of administration
Dosage form and regime
Cost
Patient population
Biological target

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17
Q

What is important to consider when using a dosage of a drug?

A

Not too concentrated that it is toxic, but not to low that it is ineffective

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18
Q

What does a drug need to be in order to get patented?

A

Novelty

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19
Q

What is the Ames test?

A

First measure of mutagenicity

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20
Q

What needs to be checked to ensure a drug is not toxic?

A

Cannot inhibit CYP450 enzymes as these are the main drug metabolising enzyme
Cannot block the hERF K+ channel in the heart as this is fatal

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21
Q

What is important to consider for neuro based drugs?

A

Amount of drug bound to free plasma protein.
Need free drug to pass over the BBB

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22
Q

How is in vitro safety and toxicology done for developing drugs?

A

Done via specalist companies, currently use dogs and rodents however beginning to move onto pigs

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23
Q

What do potential hits need to have in order to move onto the next phase of drug development?

A

Good potency
Microsomal stability
Need good bioavailability
Cannot be metabolised too much in intestine

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24
Q

What is bioavailability?

A

Bioavailability is referred to as the extent and rate to which the active drug ingredient is absorbed and becomes available at the site of drug action.

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25
Q

What was the name of the intial 11B-HSD1 inhibitor drug?

A

UE2316

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26
Q

Why was UE2316 taken through to clinical trials?

A

It passed all safety and toxicity tests
It was found to improve cognition in a mice AD model- more passive avoidance of the part of the enclosure that was associated with shocks.
There was less AB plaques in treated mice
There was a greater expression of IDE (insulin dependant enzyme) in treated mice which degrades amyloid beta

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27
Q

What is drug delivery to the brain goverened by?

A

Determined by a compound’s ability to passively transport through the endothelial cell layer, access specific uptake mechanisms or act as a substrate for pumps

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28
Q

What score determines whether a drug will cross over the BBB?

A

Pfizer- CNS MPO
CNS MPO score > 4 means it is likely to cross BBB
Takes into account the optimal physiochemical properties that will allow a drug to cross the BBB

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29
Q

How do you predict what dose will be required in humans?

A

Pharmacokinetic properties in humans cannot be measured until phase I trials
Need to use specific equasions and scaling from animal data to work out distribution and half-life
It is possible to predict in vivo clearance rates from hepatocytes
In vitro assays give the maximum metabolism rate but need to factor in human information such as plasma protein binding and liver size

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30
Q

What is important to remember about pharmakinetic parameters in rats?

A

There is a difference between males and females because the CY450 components are different
This difference is not seen in humans or dogs

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31
Q

What in vitro models can be used to check drug pharmacokinetics?

A

Pooler liver microsomes (vesicles of the hepatocyte endoplasmic reticulum that contain enzymes)
Can use these in vitro to look at stability of drugs, half life and clearance rates

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32
Q

What toxicity tests need to be passed before a drug is used in clinical trials?

A

Clear 1 month and 3 month toxicology studies in rat and 3 months in dog.
Also need CV safety in dogs, respiratory safety in rats, Irwin test in rats, hERG and mutagenicity tests passed.

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33
Q

What is the Irwin test?

A
  • The Irwin observation test is commonly used to evaluate the effects of a new substance on behavior and physiological function.
  • A range of behavioral parameters is assessed, including activity level, motor coordination, tremors, convulsions, alterations in posture, grooming behavior, and other signs of central nervous system dysfunction.
  • The Irwin test also examines autonomic functions, such as changes in heart rate, respiratory rate, pupillary reflexes, and body temperature.
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34
Q

What is pharmacokinetics?

A

Pharmacokinetics refers to the study of the time course of drug absorption, distribution, metabolism, and excretion (ADME) in the body. It involves the processes that determine how the body handles a drug, from the moment it is administered until it is eliminated.

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35
Q

What is pharmacodynamics?

A

Pharmacodynamics is the study of the physiological and biochemical effects of drugs and their mechanisms of action. It focuses on how a drug interacts with its target receptors or cellular components to produce its therapeutic or adverse effects.

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36
Q

What is the simple modelling of PK/PD based on?

A

Pharmacokinetics and pharmacodynamics
Simple model assumes there is a direct and immediate effect of the drug on its target, with no time delay between the drug concentration and its pharmacological effect.
However this is rarely the case and other factors need to be considered

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37
Q

What factors need to be considered when modelling the PK/PD?

A

It may be an intracellular target or need to cross the BBB
There may also be a lag in the max effect when compared to free plasma concentration- hysteresis

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38
Q

How could the levels of drug penetration into the CNS be measured?

A
  • PET with fluorescence labelling
  • Samples from CNS spinal fluid
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39
Q

What happened to drug UE2316?

A

The drug was sold to Actinogen, an Australian company
They renamed the drug Xanamem
There was initially no positive effect on cognitive measures in patients with AD
However a seperate subgroup analysis looked at patients with higher pTau biomarker in the blood and found it did have an effect
Phase 2b studies are currently being conducted

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40
Q

How much does it cost on average to get a drug to market?

A

$2.4 billion

41
Q

What is acute pancreatitis?

A
  • Acute inflammation in the pancreas, usually triggered by gallstones or excess alcohol.
  • 30,000 presentations each year. Affects any age or gender
  • Currently it is believed that a pathological insult such as gallstones, alcohol or drugs triggers inflammation and mitochondrial damage. DAMPs are released triggered systemic inflammation
42
Q

What are some statistics for acute pancreatitis?

A
  • In the royal infirmary in Edinburgh 8.7% of ICU beds are taken up by AP and the average length of an ICU stay is 17 days.
  • Per year in the UK it costs £200 million (old figure)
  • 75% of cases resolve but 25% get multiple organ failure. 1 in 5 of these die and no therapies for it.
43
Q

What was found to be upregulated in acute pancreatitis?

A

Molecules in the trypothan metabolic pathway including 3-HK
Pathway is important in inflammation- linked to AD and MS, diabetes and cancers

44
Q

What enzyme was targeted to help treat acute pancreatitis?

A

KMO, highly specific and converts kynureine (Kyn) to 3-HK
It is a monomeric protein that was intracellular (anchored to the mitochondrial outer membrane) and predominantly expressed in the liver, kidney, monocytic cells and microglia.

45
Q

What is important to research when chosing a drug that is blocking a pathway?

A

Whether other molecules in the pathway will be affected

46
Q

What did KMO blockade in pancreatic mice show?

A
  • Pancreatitis was induced in mice and 3HK seemed to be involved in inflammatory responses- was upregulated
  • Blocking KMO preserved the endogenous anti-oxidant pool. This was because upregulated and thus high levels of 3HK was lowering the anti-oxidant ool.
47
Q

What does druggability mean?

A

The potential of a protein to be modulated by drug-like molecules

48
Q

What factors is druggability related to?

A

The presence of accessible pockets, the overall charge and hydrophobicity of the surface
Undruggable sites include:
Those that are very small or shallow
Those that require covalent bonding
Strongly hydrophilic sites with little or no hydrophobic character

49
Q

What chemophysical properties do drug molecules need to have?

A

Need properties that will allow it to enter the body e.g. if a drug is too big and fatty will not be absorbed and if it is too polar it will be charged
If not specific will bind to other drugs and cause off target effects

50
Q

What aspects of project planning are important?

A

To have a successful project, need a clear project plan, with milestones, timelines and costs
Need a project team with good management, in house expertise, outsourced work and consultancy.
Need funding
Important to assess whether the compound should be taken forward at every stage- if it is going to fail better to stop early than later

51
Q

What information should be in a target product profile?

A
52
Q

What is the general rule of thumb for the therapeutic dose?

A

Therapeutic dose- <100mg/ day.
the range of doses at which a medication appeared to be effective and safe

53
Q

What is the IC50?

A

The dose that provides half the max response

54
Q

What does ADMET stand for?

A

Absorption, distribution, metabolism, excretion and toxicology

55
Q

When would clearance rates not matter for a drug?

A

When the drug is given as a constant intraveneous infusion.

56
Q

What is toxicology?

A

The study of the adverse effects of a toxicant on living organisms

57
Q

Who is the Grandfather or toxicology and what did they say?

A

Paracelsus 1531
“All substances are poisons; there are none which is not a poison. The dose differentiates a poison from a remedy”

58
Q

What are the different branches of toxicology?

A

Mechanistic- cellular and molecular mechanisms by which chemicals cause toxic responses
Forensic- cause of death and legal aspects
Clinical- treatments for poisonings
Environmental- where does drug go after excretion, environmental pollutants and effects on wildlife
Food- adverse effects of processed of natural food components
Regulatory- assigns risk to substances of commercial importance

59
Q

What are the different pharmaceutical products?

A

Small molecules
Biologicals
Approved drug new formulation
Drug and device combo
Approved drug new indication
Generics
Cell and gene therapies
Biosimilars
Devices

60
Q

What are biological drugs?

A

A biopharmaceutical, also known as a biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesised from biological source

61
Q

What is an example of a drug and device combination?

A

Inhaler and salbutamol for asthma

62
Q

What is an example of a approved drug with new indications?

A

Viagra was intially developed for lowering BP but now is used to treat erectile dysfunction

63
Q

What is a generic drug?

A

Majority of NHS drugs
A drug that has been on the market previously that gets taken off its patent and can be developed cheaper by other e.g. lemsip is cheaper from a supermarket brand.

64
Q

What is a bio similar drug?

A

A generic for a biological substance

65
Q

What does toxicity from small molecular and biological drugs caused by?

A
  • Small molecules are chemically synthesised, low molecular weight drugs. They are usually not immunogenic and can interact with multiple cells or organs
  • They may be metabolised to toxic intermediates and the toxicity is often off target
  • Biologicals are derived from living cells and have a high molecular weight. They may initiate immune responses as they are ‘foreign’ proteins.
  • They are usually highly targeted to specific cellular receptors and the toxicity is often due to exaggerated pharmacology.
66
Q

What was once of the consequential mass poisonings of the 20th century and what legislation did it pass?

A

The elixir sulfanliamide disaster of 1937- 105 people died
Company created a new formula of the drug dissolved in diethylene glycol which is a poison and doctors unknowingly prescribed this to patients.
No toxicology tests were done on this new formulation
In reaction to this, the US congress passed the 1938 Federal Food, Drug and Cosmetic act, which required proof of safety before the release of a new drug

67
Q

What are some of the committees in the UK and EU created for drug approvement?

A
  • The MHRA in the UK inspect labs, and gives authorisation for clinical trials to proceed.
  • The EMA gives marketing approval for EU member states and gives authorisation for multi-country trials to proceed.
68
Q

What does in vitro mean?

A

Outside the organism

69
Q

What is the current trend for in vitro drug discovery?

A

There is a push to move away from animal testing
Organoids are being created and grown however cultured cells are no where near man

70
Q

What are the different drug development phases?

A
  • PRECLINICAL- animal studies usually in rodents and dogs however there is a move towards pigs. Effects seen in animals are ~90% likely to be seen in humans too
  • PHASE I- normal healthy volunteers
  • PHASE II- evaluate the safety and efficacy of drug in patients
  • PHASE III- large patient number study to establish efficacy versus a placebo or comparator compound
  • PHASE IV- long term surveillance monitoring of adverse reactions.
71
Q

What is preclinical data for a drug used for?

A

Used to inform the starting dose and regimen, the human endpoints for monitoring, the toxicity onset and to preduct pharmacokinetic and pharmacodynamic parameters

72
Q

What is the end point of a clinical trial?

A

An event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial

73
Q

What does double-blind mean?

A

The researchers and the patients do not known if they are taking placebo or active medications/ interventions

74
Q

What happens in initial toxicology tests on animals?

A

After drug admission, after 14 to 28 days the animals are killed and the drug concentration in different tissues are analysed.

75
Q

What is involved in a phase I clinical trial?

A
  • Drug is tested to determine toxicity relative to dose and to screen for unexpected side effects.
  • 30-50 healthy volunteers
  • Doses are single or multiple ascending doses; (Single- start at 5, then 10 ect. Multiple- give 5mg for a few days, then 10 mg for a few days)
  • Not given to women in child baring age
  • Costs around £2-10 million
76
Q

What are reasons for stopping a clinical trial in phase I?

A

Half life too long or short
Poor bioavailability
Low therapeutic index
Saturable clearance mechanisms
Metabolites in humans not covered by toxicology studies
Side effects in humans

77
Q

What occurs in phase II clinical trials?

A

Looking a patient population
Tolerability and efficacy investigated
250-500 patients
$100 million

78
Q

What is involved in phase III clinical trials?

A
  • Aim is to check the efficacy and tolerability in a large number of patients different backgrounds, lifestyles and ages
  • Measure the type and and frequency of adverse drug events
  • Compare with established treatment methods and interactions
  • Measure long term efficacy in chronic diseases
  • £500 million roughly with trials all over the world
79
Q

What is involved in Phase IV trials?

A

Drug is placed on the market and patients are monitored for side effects

80
Q

What is pharmacovigalence?

A

The science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medicines and biological products to identify potential new hazards and prevent harm to patients

81
Q

What is Mavacamten?

A

A selective and reversible inhibitor of the cardiac myosin ATPase. This decreases contractions
Indicated for heart failure and obstructive hypertrophic cardiomyopathy

82
Q

Who created Mavacamten?

A

It was a novel drug created by MyoKardia Inc. a subsidiary of Bristol Myers Squibb

83
Q

What does orphan status of a drug mean?

A

The FDA has authority to grant orphan drug designation to a drug or biological product to prevent, diagnose or treat a rare disease or condition
- Gives companies incentives to develop drugs for rare diseases that will not necessarily cause a large profit gain by tax incentives and marketing exclusivity.

84
Q

What happened to the toxicology studies of mavacemtan?

A

Observed adverse effects were seen in both rodents and dogs (lung and liver injury) and these effects were seen at doses below clinical therapeutic exposures
Ferticology toxicology studies indicated a high risk of adverse effects in offspring
The drug was still taken to clinical trials- during these plasma drug concentrations were monitored strictly and effects in patients which led to dose adjustments when neccessary

85
Q

How long does the drug discovery process take on average?

A
86
Q

What are the minimum duration of toxicology animal studied needed for different durations of clinicl trials?

A
87
Q

What is the current gold standard for toxicology animal testing?

A

Dog is the gold standard but this is changing

88
Q

What are the pros and cons for using mice in toxicology studies?

A
  • Has a large historical database and well characterised biology. It is also inexpensive- costs around £10 per mice
  • However, mice are sensitive to environmental changes, have high metabolic rates (ADME differences) and so small they cannot take enough blood to use in toxicology
89
Q

What are the pros and cons for using rats for toxicology studies?

A

Also has a large historical database and well characterised biology. Cheap= £12-15 per rat
Differences in males and females in drug metabolism due to different CYP450 enzymes

90
Q

What are domestic rabbits most commonly used for in toxicology?

A
  • These are more commonly used for ocular toxicology and reproductive toxicology
  • Historically used in cosmetic testing however this is not done in Europe or the Uk anymore
91
Q

What are the pros and cons of using dogs in toxicology?

A
  • The beagle is the most widely used non-rodent research animal
  • There is an extensive historical database for small molecule development
  • Pressure to limit use- some companies have stopped using dogs and animal activists closed down a site in England and dogs now come from abroad
92
Q

What is the pig used for mainly in research?

A

Drug testing and toxicology slowly increasing
Research into organ transplantation and surgical research also done

93
Q

What are the pros and cons of doing toxicology studies on non-human primates?

A
  • Phylogenetically and physiology more homologous with humans and the immune system is similar to humans.
  • They are costly and limited resource- COVID had a huge explosion of testing, China stopped exporting monkeys and huge demand meant they increased in price from £5000 to £25000 per animal
  • Need very good scientific justification for using primates with ethics committees
94
Q

How is AI used in toxicology studies?

A

Big pharma has large library of compounds and AI can look at these and decide which to take forward in which species

95
Q

What was the TeGenero incident?

A

Cytokine storm was induced in 6 men who volunteered to take part in a phase I trial of a novel Anti-CD28 monoclonal antibody TGN1412
4 volunteers went into multi-organ failure and whilst they all survived, one volunteer had to have his fingers amputated

96
Q

What caused the TeGenero incident?

A
  • MHRA concluded a unpredicted biological action of the mAb in humans was most likely the cause of the adverse reaction
  • The preclinical studies did not predict a safe dose for use in humans and new guidelines were created from this incident. The company trialled too high a dose and flooded the receptors. They should have dosed lower- 100mg should have been 0.5mg.
    Turns out the receptor was not activated in animal species- made selecting the correct species even more important
97
Q

What were the outcomes of the TeGenero incident?

A

Now no phase 1 unit can be conducted away from a hospital.
Now the limit for dosing is set alot lower and even lower for biological drugs now
The company went bust due to pay outs from the scandal

98
Q

Why is selecting the right animal important for preclinical trials based on the TeGenero incident?

A

The receptor activated in humans was not activated in the animal species
- The test material in the animal should be pharmacologically active due to the expression of the receptor. A variety of techniques e.g. immunochemical can be used to identify a relevant species. Knowledge of the receptor distribution can also be important and provide greater understanding of potential in vivo toxicity.

DRT and synoptic exam revision (9 decks)

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