Drug development Flashcards

Question

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

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

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

Answer 7

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.

Answer 8

- 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.

Answer 9

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.

Answer 10

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.

Answer 11

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

Answer 12

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

Answer 13

- PET with fluorescence labelling - Samples from CNS spinal fluid

Answer 14

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

Answer 15

$2.4 billion

Answer 16

- 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

Answer 17

- 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.

Answer 18

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

Answer 19

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.

Answer 20

Whether other molecules in the pathway will be affected

Answer 21

- 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.

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

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

Answer 27

The dose that provides half the max response

Answer 28

Absorption, distribution, metabolism, excretion and toxicology

Answer 29

When the drug is given as a constant intraveneous infusion.

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

Inhaler and salbutamol for asthma

Answer 36

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

Answer 37

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.

Answer 38

A generic for a biological substance

Answer 39

- 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.

Answer 40

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

Answer 41

- 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.

Answer 42

Outside the organism

Answer 43

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

Answer 44

- 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.

Answer 45

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

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

- 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

Answer 50

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

Answer 51

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

Answer 52

- 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

Answer 53

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

Answer 54

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

Answer 55

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

Answer 56

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

Answer 57

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.

Answer 58

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

Answer 59

Dog is the gold standard but this is changing

Answer 60

- 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

Answer 61

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

Answer 62

- 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

Answer 63

- 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

Answer 64

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

Answer 65

- 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

Answer 66

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

Answer 67

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

Answer 68

- 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

Answer 69

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

Answer 70

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.