8/16/16 Drug Discovery/Devpt - Banerjee Flashcards
what is a drug?
- any molecular/chemical entity that is useful in either diagnosis or treatment of a disease (humans or animals)
- needs to be SELECTIVE in its action
drug discovery process/timeline
- develop ASSAY : evaluate activity of compounds on target
* in vitro vs. in vivo - identify a LEAD COMPOUND
* screen from variety of sources (compound library, publications, naturals, rational-drug-design) - optimize to provide PROOF-OF-CONCEPT molecule : shows efficacy in animal-disease model
- OPTIMIZE to give favorable DRUG QUALITIES
* PK, metabolism, side effects - SAFETY ASSESSMENT [safe and at least as good as what’s out there]
and now it’s a PRECLINICAL CANDIDATE!
in vitro study goals
- molecular mech of action at specific drug targets
- molecular pharmacology
- determinants of response
- intracellular PD
- mechanisms of resistance
in vivo study goals with animal models
efficacy : proof of therapeutic principle
toxicology : tox profile
practical issues
- animal PK and PD
- starting dose/schedule for clinical trials!
IND
what is it?
what does it allow you to do?
Investigational New Drug
application submitted after preclinical trials → if approved, can pursue phased clinical trials!
phase 0 trials
why have them?
what are they?
what are the limitations?
40% fail in Phase I bc of unsuitable PK
- it would be a lot more efficient and cheap if we could identify some of these 40% before getting into Phase I
- enter…Phase 0!
use a homeopathic dose of drug, admin to small cohort of patients, look at a marker that serves as a surrogate for the drug so that you can get an indication of whether the drug will make it through I, II, III
limitations:
- drug must have a wide therapeutic index
- target must be known and a validated biomarker must exist
- for patient:
- not at therapeutic dose
- has no therapeutic outcome
- cant participate in any other type of treatment
- ethical concerns of all of the above
phase I trials
looking at?
who participates?
what are you trying to determine?
ADME : absorption, distribution, metabolism, excretion
looking at 20-100 patients:
- normal volunteers
- patients with disease
- also subpopulations (elderly, liver disease, etc)
- common clinical settings (food effects/drug interactions)
make use of tolerability and dose escalation designs to determine MTD (max tolerated dose)
- often use Fibonacci dose escalations
phase II trials
who and how many?
whats the point?
therapeutic exploratory studies
explore efficacy and safety in patients (100-1000 individs) with target disease
hypothesis generating studies
estimate dosage, explore methodology, look at endpoints for definitive studies
phase III studies
therapeutic confirmatory studies
confirm efficacy and safety profile in target pop
provide adequate basis for assessing risk/benefit relationship to support regulatory approval
- point: SAFETY and EFFECTIVENESS have to be proved
- proving that it’s BETTER - not required!
typically involves a broader pop (>1000)
NDA
new drug application
following phase I, II, III clinical trials
if approved, can launch new drug on the market → remains under surveillance for adverse effects!
phase IV studies
performed to determine whether a drug is safe over time and/or to see if a treatment or medication can be used in other circumstances
aka post market surveillance
important! can lead to withdrawal of drugs from market (ex. Vioxx) due to adverse effects!
withdrawn from market:
COX2 inhibitors!
story and why
COX2 selective drugs : alternative to non-selective NSAIDs (which can cause stomach/kidney/GI issues)
COX2 inhibitors strictly inhibit cyclooxygenase2, enzyme primarily responsible for inflammation and pain
- issue: saw increasing reports of adverse cardiac events with COX2 inhibitors
-
why? target prostacyclin (vs thromboxane)
- thromboxane presence = platelet aggregation
- add vasoconstriction
- CARDIAC EFFECTS!!!
CELECOXIB (Celebrex) survived the pull of COX2 inhibitors from market
why?
all comes down to specificity for COX2!
- valdecoxib/rofecoxib (Vioxx) - 300x more specific for COX1 than COX2
- etoricoxib - 106x
- celecoxib - 30x
