Drugs Flashcards
The probability of successful transition to the next stage of drug development
P(TS)
In drug development, WIP means
Work in Progress
In drug development, NME means
New molecular entity
For drug discovery, we want to develop an assay to evaluate activity of compounds on the
Target
Then we want to identify a
Lead compound
Then we use animal models to optimize the lead compound to give a
Proof-of-concept Molecule
Then we optimize to give the compound
Drug-like properties
When we study this drug in vitro, we want to define the drugs
Pharmacology
In vitro studies (i.e. cell lines), drug formulation, and drug chemistry are examples of
Components of non-clinical drug development
Used to show efficacy of the drug
In vivo studies on animal models
Pharmacodynamics, pharmacokinetics, drug interactions, and receptor sensitivity are examples of variables in
Clinical trials
Once the preclinical studies are completed, we submit an application to the FDA called
IND or investigational new drug
Allows you to pursue phased clinical trials
IND
It is estimated that what percentage of drugs fail in phase I trials because of unsuitable pharmacokinetics?
40%
These unsuitable pharmacokinetics are determined in
Phase 0 trials
The drug must have a wide therapeutic index and the target must be known, with a validated bio marker in order to be tested in
Phase 0 trials
No therapeutic benefit can be conferred by the small doses given in a
Phase 0 study
While taking part in a phase 0 study, patients are not allowed to enroll in a trial with
Therapeutic intent
Studies ADME: Absorption, Distribution, Metabolism, and Excretion
Phase I trials
Performed on normal volunteers, in patients with target disease, in subpopulations (elderly, liver impairment) and in common clinical settings (food effects, drug interactions) (20-100 individuals)
Phase I trials
Phase I trials have dose escalation designs to determine
Maximum Tolerated Dose (MTD)
Fibonacci dose escalations are often used in
Phase I trials
Classified as therapeutic exploratory studies
Phase II studies
Classified as human pharmacology studies
Phase 0 and I studies
Explore efficacy and safety in patients with target disease (100-1000 individuals)
• Estimate dosage for definitive studies
Phase II studies
Explores endpoints and study methodologies for definitive studies
Phase II studies
Called therapeutic confirmatory studies
Phase III studies
Used to confirm efficacy and safety profile in target population
-Provide adequate basis for assessing benefit- risk relationship to support regulatory approval
Phase III studies
Provide adequate basis for assessing benefit- risk relationship to support regulatory approval
Phase III studies
Following successful completion of clinical trials the investigators submit a
NDA: New Drug Application
Done to determine if a drug or treatment is safe over time, or to see if a treatment or medication can be used in other circumstances
Phase IV clinical trials
Done after a treatment has gone through phase I, phase II and phase III trials, and is already approved by the FDA. This is called post market surveillance
Phase IV clinical trials
Were created as an alternative to non- selective NSAIDs to decrease stomach, kidney and gastrointestinal problems commonly associated with these drugs
COX2 inhibitors
The mechanism of action of Vioxx and other drugs in the same class is believed to be through strictly inhibiting cyclooxygenase 2, the enzyme that is primarily responsible for
Inflammation and pain
Inhibiting strictly COX 2 enzymes creates an imbalance in favor of COX 1 enzymes resulting in a greater likelihood for
Platelet aggregation and endothelial constriction
The only remaining COX2 inhibitor available because of lower specificity for COX2 over COX1
Celebrex/Celecoxib
