Midterm 1 Flashcards
what does a “hit” refer to in the drug discovery process
a potential compound that may have therapeutic effects, may be found through high throughput screening
what does a “lead” refer to in the drug discovery process
a hit that has optimal effects and will be tested in vivo/in vitro. while you may have thousands of hits, you only have 10-20 leads
what are the main concerns with pre-clinical testing
determining the Pharmacokinetics (ADME), the safety, efficacy, and dosing range
half life of a compound
toxicity tests (single dose/acute, repeated dose (chronic and sub-chronic), reproductive, developmental, carcinogenic)
determine elimination routes
most drugs fail in which phase of clinical trials
three - is the drug more effective than placebo
what does Health Products and Food Branch of health Canada do
regulate all health products - including pharmaceuticals, medical devices, natural health products, veterinary medicines, foods
the branch of health canada concerned with prescription medication
Pharmaceutical Drugs directorate
review process
manufacturere creates a new drug submission request with the Health Products and Food Branch, submitting information about pre-clinical and clinical trials, the claimed therapeutic effects and side effects, and information about production/packaging, and labelling. the HPFB reviews all this informatin, consulting external committees if necessary, and determines if health benefits outweigh the health risks as well as if the product label is sufficient. IF they decide the benefits do outweigh the risks, the product recieves a notice of compliance and a DIN. if a drug is not approved, it can ask for reconsideration or gather additional information and resubmit their request at a later date
what is the Lot Release Process
additional screening of each lot of manufactured products before they’re sold
the review by health canada usually takes
300 days, expedited reviews for life threatening conditions aim for 180 days
orphan drugs
those used to treat very rare conditions - often get expedited reviews
drug development to release to market takes roughly how long
15 years
what is the ICH
international council for harmonization of technical requirements for pharmaceuticals for human use
what does the ICH do
collaborate between nations to reduce the duplication of clinical trials, and create guidelines about the manufacturing, development, and testing of new pharmaceuticals
when was the ICH officially formed
2015, though nations began banding together with the common goal in 1990
what is the timing of an acute/single dose toxicity test
single dose administered (or multiple doses all in one day) and the effects are observed for 14 days
how long do sub-acute (repeated dose) toxicity tests last for
28 days
how long do sub-chronic toxicity tests last for
90 days
how long do chronic toxicity tests last for
6 months - 2 years
what is the main purpose of an acute toxicity test
tells you the LD50
potential for acute toxicity in humans and what it looks like (time course, signs/symptoms/target organs
species differences in tox
important things to know about your drug before you begin testing
chemical form and properties so you can presume its solubility
data on previous similarly structured chemicals (if possible)
procedure for acute oral toxicity testing
test animals sequentially beginning at the high end of the scale (one level below the suspected LD50). if the first animal lives (48 hours later), you increase the dose by one step, if it dies you decrease the dose by one step
when do you stop acute toxicity testing
when three consecutive animals survive at the upper bound of the toxicity scale (usually around 2000-5000 mg/kg)
when 4 animals have followed the first reversal (OXOXOX) and two likelihood ratios
five reversals in any 6 consecutive animals tested
what do you do if an animal unexpectedly dies in your acute tox test
stop all dosing and observe all animals to see if a similar effect occurs, if they also die, restart the study and begin at least two steps below the lowest dose that caused the death
what kinds of animals are used in acute toxicity studies
ideally female rats who are not/have never been pregnant, are 8-12 weeks old, and are all roughly the same weight. they should be individually housed until 48 hours post dosing, then they may be returned to the group hoiusing
ideal dosing in toxicity studies
should always use the same volume of dose
ideally prepared in water
fast animals before dosing - rats overnight, mice 3-4 hours before, and after dose for 3-4 hours for rats and 1-2 for mice
observations for acute toxicity studies
at least once in the first 30 minutes, periodically in the first 24 hours (at least four times), daily thereafter for 14 days
what are sub-chronic toxicity tests used for
assess the potential toxicity from daily exposure from 28-90 days, simulating a more common method of toxicity (most drugs cause toxic effects after building up in your system over time)
identify maximum tolerated dose
gives insight into the appropriate doses for chronic and carcinogenic studies
maximum tolerated dose
highest dose that can be given chronically without harming the subject
how many rats do you want to use for sub-chronic toxicity testing
20 - 10 in each sex group
satellite groups
groups of animals you are just using to gain additional information about pharmacokinetics/take blood from
how should the dosing work for sub-chronic toxicity testing
three seperate dose levels - the highest of which should cause toxicity but not death. start with the highest dose and descend in two or four-fold intervals
animals dosed seven days a week for 28 or 90 days
observations in sub-chronic toxicity tests
checking daily to see if it is suffering/dying and to note changes in its appearance or habits
weekly - check its weight and food consumption
do hematology and clinical biochemistry tests, as well as an autopsy at the end of the study
how does chronic toxicity testing work
12 months of daily dosing with at least three groups of dose levels descending by 2x or 4x
ideally orally administered to 40 animals (20 of each sex group)
observations for chronic toxicity testing
twice daily for mortality or morbidity
daily general clinical observations
body weight and food consumption weekly for the first 13 weeks, monthly thereafter
hematological exams at 3, 6, 12 months
autopsies for all
when are carcinogen tests not required
when the drug is to be used for less than 6 months
when the life expectancy of the target population is less than 2-3 years
if the drug is a replacement therapy of an endogenous substance
what may flag a compound for carcinogenic concerns
the product class has carcinogenic potential
the structural - activity relationship program flags it
paraneoplastic lesions are found in repeated animal dose studies
there is long term retention of parent compounds or metabolites
how many animals for a carcinogenicity study
50 per sex group, 2 year long study using dose previously determined in your repeated dose studies
outcome of interest in male reproductive studies
sexual behaviour, libido, fertility, pregnancy outcomes
outcomes of interest in female reproductive studies
sexual behaviour, libido, onset of puberty, fertility, gestation, parturition, lactation, premature reproductive senescence
when are developmental toxicity studies requried
if the drug can be used by females of reproductive potential
three segments of developmental toxicity test
1: fertility and general reproductive performance: test both male and female rats
2: teratology or embryo/fetal toxicity: in rats and rabbits
- perinatal and postnatal development: in rats to determine the drug effects during the last trimester and during lactation
list what is contained in the three clinical trial application modules
1: administrative information, information about participant recruitment (where, who, how many), information from animal trials
2: quality information (chemistry and manufacturing)
3: supporting information
declaration of helsinki
world medical association agreement about ethics in human research - primarily to protect the health, interests, and confidentiality of research subjects
phase one clinical trials
main concern - is it safe for humans
- around 80 HEALTHY volunteers for several months - a year
- can use patients in extreme conditions but the test is not designed to treat at this point
- want to identify the maximum tolerable dose
maximum tolerated dose
the dose which will not cause severe side effects/ toxicity or impact the survival of the organism
phase II clinical trial
is it effective? usually 1-2 years with 100-500 patients
phase III clinical trials
is it more effective than placebo? 1-4 years long with 300-3000 patients. Looking for long-term or rare side effects
who prevented the thalidomide crisis from being a thing in the USA
Frances Oldham Kelsey
things the standard council of canada may assess to evaluate good labratory practice
- personnel are well trained and responsible
- testing facility is adequate for its purpose
- equipment and materials are up to standard and labelled properly
- the product is studied on a batch basis - for stability, purity, composition
- people are aware of the standard operating procedure
- animals in use are cared for properly
- everything is properly documented
what is the Standard Council of Canada (SCC)
the monitory authority for GLP compliance of testing facilities
what is the regulatory operations and enforcement branch (ROEB)
the regulatory agency responsible for inspecting and investigating clinical trials in Canada
good CLINICAL practice
for human research, regulated by the ROEB
- research should be conducted in accordance with the declaration of Helsinki
- research is based on adequate non-clinical studies (theory is sound)
- protocols approved by the ethics board
- risk analysis before and during the trials
- use qualified medical professionals
- get informed consent and keep participants information confidential
- immediately report serious adverse side effects
who does the sponsor refer to in clinical trials
the company/institution/organization which takes responsibility for the initiation, management, and financing of clinical trials
who is the clinical investigator in clinical trials
the physician responsible for conducting the trials at the site
what is the CCAC
Canadian Council on Animal Care
- national council that provides guidelines for the basic requirements for institutional animal care
- each institution will have an animal care committee accredited by this council to review and monitor animal studies
what are the main concerns of animal care committees at institutions
make sure the study is well thought out and important, are the use of animals absolutely necessaryt
Three R’s in the use of animal studies
replacement - can it be done in vitro instead
reduction - can you use less animals
refinement - can you minimize the pain and suffering of the animal
describe the 5 purposes of animal use (PAU)
1 - fundamental science studies for essential structures or functions (uses the most animals)
2 - medical (vet or human) studies relating to disease and disorders
3 - regulatory product testing
4 - development of products or appliances for medicine (uses the second most animals)
5 - education and training of individuals in institutions
categories of invasiveness for animal experiments
A - experiments on invertebrates or live isolates
B - Little or no discomfort
C - minor stress or pain of short duration
D - moderate - severe distress or discomfort
E - severe pain that exceeds the tolerance of the animal
list some canadian laws and regulations regarding the use of animals
sec 446 and 447 of the Criminal Code of Canada - cannot abuse/neglect animals
health of animals act - prevent disease outbreaks
spending power - special grants for ethical animal research
veterinarian act of sask - exemptions made for universities whose animal care committee contains a vet
ideal animal model (biological standpoint)
the ADME and characteristics of animal responses to treatment are close to that of humans
stages of life of the animal are close to that of humans
there is a close phylogenetic relationship to humans
ideal animal model from a technical standpoint
low body weight, easy to bleed and large enough to collect a reasonable supply of blood, easy and inexpensive to handle/breed/dose, short lifespan
limitations of animal models
differences in ADME and anatomy of the animal from humans
different strains of the same species may generate different results
the nature of pathological responses may differ at all levels (subcellular, cellular, receptor)
the dose required to produce results in animals is never the same to that in humans
the characteristics or conditions of interest in humans may not always be replicated in animals
commonly used species in animal testing
rats/mice: easy to handle and breed, well understood and accepted by science, rapid metabolism and lower systemic exposure
rabbits: phylogenetically similar to humans, similar cardiovascular system, used often for ocular and dermal irritation tests, but harder to house and handle
mini-pigs: human-like kidneys - not easy to handle
zebrafish - embryos can be used for developmental toxicity screening, if they are younger than 120 hours post-fertilization they do not qualify as animal testing - but they are hard to dose since they are aquatic and so small
advantages of in-vitro testing
highly standardized and controlled
fast, inexpensive, less materials used and less waste produced
human cells and tissues can be used
reduces animal testing
limitations of in-vitro tests
cannot test interactions between tissues or organs
cannot evaluate systemic effects
dose-responses in-vitro not valid for in-vivo human use
what is Reconstructed human epidermis used for
an in-vitro skin irritant test which uses human derived non-transformed keratinocytes to create a medium that closely matches the biochemical and physiological properties of human skin
what are SIRC rabbit cells used for
cornea cells from the rabbit to test ocular cytotoxicity
micro-physiological systems
a micro recreation of human organ compartments used to evaulate how a chemical interacts wtith that body system - FDA approved to test hepatotoxicity, drug metabolism/transport and intracellular accumulation
in-silico toxicity models
quantitative structure activity relationship models that predict adverse effects based on the molecular structure of the compound
