module 1 Flashcards
name and explain the 2 types of drugs
Biologics
- vaccines, proteins, nucleic acids
- high molecular weight
- manufactured through living organisms
Small molecules
- low molecular weight
- manufactured using living organisms + chemical synthesis
- where most money is spent
describe pharmaceutical companies
- invest heavily in research
- discover + develop new molecular entities
- large companies
describe generic pharmaceutical companies
- limited investment in research
- do not discover new entities
- adapt or circumvent patents
- specialize in methods + formulation
- large to medium sized
describe biotech companies
- exploit academic discoveries
- invest heavily in research (not on market)
- smaller companies
- exist shortly, taken over by larger companies
describe contract research organizations (CRO’s)
- specialized services: testing, synthesis, manufacturing, research
- contact clinical trials
- small companies
how many new molecular entities are approved each year?
around 40
explain the difference between molecular entity and product
molecular entity: pure active ingredient
product: formulation that contains molecular entity
formulation includes API (active Pharma ingredient + excipients)
how much time does it take to create a new molecular entity?
12 years average
list and describe the 5 stages for the formulation of a new molecular entity
discovery
1-3 years
start with an idea, drug candidate identified
development 1-2 years
drug candidate into sellable investigational new drug
clinical trials
1-5 years, 3 rounds
drug tested in humans for safety and efficacy
new drug application filed
FDA approval
6 months to 1.5 years
Market
describe drug candidate
- identified 1-3 years after research
- driven by chem + biochem
- data is confidential
- animal testing needs ethical review
- no approval needed for most testing, enters development
describe IND
- investigational new drug
- application to FDA to start clinical trials
- Includes pharmacology and toxicity data from animal to ensure safety
- manufacturing information to ensure consistency: method + purity profile
- Plan for clinical trials and investigator info
describe NDA
- new drug application
- application to FDA to enter market
- safety
- efficacy: do benefits outweigh the risks
- labelling
- info from human and animal trials
- manufacturing: reproducibility, maintain quality
describe ANDA
-abbreviated new drug application
- application to FDA to enter market as generic version of drug
- Data showing that the drug identity, dose, formulation, route of administration, and performance are included
what are the 2 most common methods used to identify leads
- High Throughput Screening HTS
- Rational drug design
- Natural products
Describe HTS testing
- quickly tests a large number of compounds for biological activity
- compound tested at same dose
- assay provides yes/no response
- use variety of compounds (structures + chem types)
- hit: positive response
- most hits false: impure, decomposition, reactivity
- retest using purified samples at multiple concentration
what are PAINS and their role in HTS
- pan assay interference compounds
- major source of false positive in HTS
- show activity in virtually any biological test
- interfere with tests by reacting with biological targets
- mechanisms include: detergents, strong acid/base, nucleophile/electrophile
describe re-testing hits and concentration dependent manner
- based on the principle that compounds interact with biological targets in a concentration-dependent manner
- dose-response curve typically shows an increase in effect as the concentration increases, often following a sigmoidal shape
- fail to show a dose-dependent response may be eliminated as false positives
describe the hit to lead process and how much time it takes
- requires 3-6 months
- HTS, yes or no response
- counter screen to reject non specific
- database search to reject pains
- routine assay/dose response to reject compounds that do not show dose response
- purification, resynthesis, retest, reject compounds that mis behave
- synthesize + test analogs, reject compounds that don’t show SAR (Structure-Activity Relationships)
features of drugs developed by HTS
- aromatic rings, easy to change
- no defined stereochemistry (stereogenic centres)
describe natural products
- chemicals isolated from plants, animals, microbes
- chemicals are secondary metabolites, not required for life, used for secondary purpose such as: poison, colour, fragrance
Describe SAR
Structure activity relationships
- involves making small changes in a drug structure and observing the resulting changes in biological activity
to:
- to optimize drug properties
- identify parts of drug that interact with target
describe the difficulties in using natural products
- require large amount of source
- difficult to perform SAR (Structure-Activity Relationships) as they have complex structures
- limited to only chemical modification
features of natural product structures + example
- aliphatic
- sterocenters
- lots of functional groups
example: penecillin
describe rational drug design
- design lead using known chemical structure
ex: enzyme substrate, inhibitor, existing drug - knowledge of mechanism
features of rational drug design molecules + examples
- active part ace inhibitor in catopril which regulates BP, starting point is venom
- acyclovir used to treat herpes resembles guanine, transforms in the body to become active
- aromatic + aliphatic
- limited stereochemistry + functional groups
what processes are used for lead optimization? describe each
- SAR and SPR
Describe the difference between SPR and SAR
SAR:
- tests molecule activity
- determine relationship between structural modifications and activity
- how to optimize or come up with new
SPR:
- variety of tests, multiple variables to consider
- optimize several properties:
- potency: lowest dose possible
-selectivity: ratio between dose that gives desired biological activity vs undesired, high selectivity is rare (BENEFITS OUTWEIGH THE RISKS),
- solubility in h2o, chemical stability, toxicity, synthesis ease, acid base behaviour
What is the end result of the discovery phase?
- turn lead to drug candidate
- requires 1-3 years
- chemical properties known
- basic biological profile is known
- backup compounds are identified
What is the end result of the development phase?
- turn drug candidate into sellable product (investigational new drug)
- FDA approval to start clinical trials
- determine safety for humans
- confirm activity
- large scale manufacture process
- formulation
what are the 3 requirements for a patent
novelty
- new invention/discovery
utility
- be used for a purpose
non-obviousness
- not an obvious solution or idea
describe process chemistry + company goals for this
- establish methods for large scale synthesis (reactions don’t work the same on large scale as small scale)
- limited purification methods: crystallization and distillation
- regulated by good laboratory practice
- optimize synthesis for lowest cost
what are the FDA requirements for large scale synthesis?
RELIABILITY;
constant yield
constant purity
constant purity profile (same impurities in same proportions)
describe how drug companies perform safety testing during drug development phase?
safety testing I in vitro
- no living organism, in test tube or petri dish
- as many biochemical assays as possible (usually tested by CRO’s)
- minimize positive results
- drop lead for deal breakers: carcinogenicity, interference with organ function
safety testing II (in-vivo)
- smallest sized animals (less drug)
- fewest animals (less money)
- 2 species (AT LEAST ONE PRIMATE FOR HUMAN SIMILARITY)
- rats + dogs
describe excipients and list some examples
- non medicinal ingredients, usually from food industry
- stabilizers: acid/base protect from degradation due to oxygen
- preservatives : prevent bacteria or mold
- disintegrates: help deliver drug, starch
- flavours: sweetness for kids, safety in adult medication
- colours: safety and identification
- fillers: ensure correct dosing, cellulose, MgSO4
give examples of types of formulations
-pills, capsules, liquids
- digested orally
topical cream, patch, nasal spray, eyedrops
- bypass liver, if ingested may not reach bloodstream fast enough
Nuremberg code for research on humans
- voluntary participation
- informed consent
- prior animal studies
- benefits must outweigh the risks
- done by qualified scientists
- no unnecessary suffering
- must stop if become dangerous
Describe phase I of clinical trials
- less than a year
- small #, healthy volunteers
- focus on safety only
- main purpose to find MAX safe dose
- 30% fail
Describe phase II of clinical trials
- less than a year
- small number of patients
- effective dose
- focus on safety and efficacy
- 70% fail
Describe phase III of clinical trials
- large number of patients
- safety and efficacy
- look for rare side effects
- 70% fail, 6% pass
What happens after phase 3 of clinical trials?
- IND - NDA
- new drug application filed for market approval
- FDA review takes 6 months to 1.5 years
Describe early government regulations surrounding drugs
before 1907: completely unregulated
1907: board of food and drug inspection
- focused on labelling (list of ingredients)
1938: food and drug administration
- establish to ensure safety
- FDA established
- animal testing (except species type) + clinical trials now required
- directions for proper use now required
Describe orphan drugs
- for rare conditions (less than 200,000 ppl affected)
FDA encourages this through:
- faster + smaller clinical trials
- 7 year market exclusivity
- tax credits of up to 50% of research costs
Describe modern safety standards in animal testing for humans
- 2 species
- 1 must be primate
- show that drug is bioavailable (gets in body)
- must use relevant dose
Describe the theory of teratogenicity for thalidomide + its mechanism
- drug was sold as racemate (2 stereoisomers possible)
- s enantiomer was teratogenic
SEE MECHANISM
How does the FDA function?
- all testing is done by companies, provide full data to FDA
- inspect to make sure it meets guidelines –> approval
- FDA requires companies to monitor products + report any problem
- FDA provides inspections for manufacturing
5 major phases of discovering new drug
- discovery
- development
- phase I
- phase 2
- phase 3
