drug discovery Flashcards
What is a recent example of drug-drug interactions?
Sorivudine - antiviral, inhibition of 5-flurouracil metabolism
Terfenidine - antihistamine when coadministered with ketoconazole lead to cardiotoxicitiy
What are recent examples of unexpected toxicity?
troglitazone - severe hepatoxicity
Rofecoxib - selective COX-2 inhibitor increased risk of CVD/stroke
What is the main reason for failure during drug development?
innappropriate pharmacokinetics
lack of efficacy
What are some examples of drugs developed from herbal/traditional remedies?
morphine from opium
diogoxin/digitoxin from foxgloves
salicyclic acid from willow bark
What are some drugs discovered from the empirical approach?
anticancer drugs
cyclosporin (immunosuppressent)
What is the empirical approach?
development of models felt to be predictive of activity from the screening of a large number of compounds
What is rational drug design?
understanding the cellular/molecular basis of disease using computer technology.
e.g propanolol (beta blocker)
What are examples of prodrugs?
aspirin (salicyclic acid)
paracetamol (phenacetin)
What is serendipity?
a chance observation
e.g penecillan or sildenafil (viagra)
What does the preclinical phase involve?
in vitro/in vivo animal studies
tests, biological activity, toxicity, safety, PK/PD and ADME
What info do we get from the preclinical studies?
safe starting dose carcinogenic potential? PK/PD relationships Linearity of PKs excretion metabolites absorption
Why di the PKs need to be linear?
because saturation of metabolites = non linear
What does phase 1 involve?
small number of healthy volunteers.
tolerated dose, toxicity, PK/PD
What does phase 2 involve?
several hundred patients with specific disease. Therapeutic effectiveness (dose/conc/response) short term safety
What does phase three involve?
several thousand patients
clinical safety and efficacy
refine dose/conc etc
qualitative and quantitative assesment of ADRs
