Drug Dev/Laws Flashcards
Preclinical Trials
DISCOVERY
okay’ed on animals- ID potential RISKS and TOXICITY in 2 diff species
ID max dose and lethal dose
Clinical Trials - Phase 1
SAFETY
done in healthy volunteers
Clinical Trials - Phase 2
EVALUATE EFFICACY and ACTIVE DOSES
done in 100 pts with disease/condition
short-term S/E and tox
Clinical Trials - Phase 3
CONFRIM EFFICACY and SAFETY
1000 pts with disease
usually inc toxicities are seen
Phase 4
Goal: ESTABLISH Safety & Tolerability
Pharmacokinetic Principles
What influences absorption rates?
- or - charge
- lipophilic
- site of absorption
- Formulation
- Bioavailability
Oral administration
Absorption: variable
convenient
IM
Absorption: Rate depends on drug formulation and blood flow
Painful
IV
Absorption: Immediate effect
Good for emergencies and large volumes of meds
Inhalation
Absorption: Rapid lung absorption
Gets to site of action with minimal systemic effects, need good technique
Transdermal
Absorption: Formulation dependent
Convenient, prolonged release with constant levels
Topical
Absorption: Poor systemic absorption
good for derma, opthalmic, nasal, otic meds
Dosing not as precise
What population is volume of distribution important?
Obese, pts with a lot of fluid, or known to have a high vol dist need to have a higher drug conc
Define prodrug?
Must be broken down by the liver to be converted to active metabolites *First pass effect
Take into accnt pts liver
First pass effect
Orally admin drugs metabolized significantly resulting in significant reduction in dose reaching the circulation
Phase 1 rxn
- creates a lipid soluble cmpd -> water soluble cmpd
ex: oxidation via cytochrome P450
Significance of Cytochrome P450
Pathway drug MUST take to be broken down.
- Induction: increase metabolism/excretion of drug -> dec therapeutic effect
ex: Rifampin - Inhibition: decrease metabolism/excretion of drug -> inc effect
ex: Erythromyocin + Sumvastin
-AZOLE P450
1A2, 3A4 Inhibitor
AMIDARONE P450
3A4 Substrate
RIFAMPIN P450
1A2, 3A4, 2C9, Inducer
PHENYTOIN P450
2C9 Substrate
3A4, 2C9 Inducer
FLUOXETINE P450
2C9 Substrate
Phase II RXN
produce a metabolite with improve water solubility
- elimination of drug from tissue
ex: glucronidation, sulfation - –Acetaminophen metabolism uses both
Steady-state conc
time to steady state is independent of conc
it is attained after ~ 4 half lives
