Profiling opportunities during the drug discovery process

Question 1

• Target distribution

Answer 1

o receptor may be expressed in organs other than those intended for therapeutic modulation
o does action at other receptors cause unwanted side effects?

Question 2

• Gene knock-out

Answer 2

o Genetic manipulation may show direct side effects

Question 3

• siRNA approach

Answer 3

o silencing the target in specific organs can provide information about whether the drug is causing the toxic effect and confirm the role of the target in a toxicological outcome
* Enantiomers may be inactive but has the same structure, so the potential for chemistry-related toxicity is equivalent
 

Question 4

• Single dose toxicity

Answer 4

o The effect of a single dose is observed
o Two mammalian species are studied
o Effects of dose observed for 14 days then mortality is recorded
o Morphological, biochemical, pathological and histological changes are investigated

Question 5

• Repeat dose toxicity

Answer 5

o Two mammalian species are studied
o Long duration (30-180 days)
o Dose is dependent on dose escalating studies (3 different doses given)
 High dose 10x the maximum clinical dose
 Low dose 2x clinical dose
 Medium dose midway between low and high dose

Question 6

o Drug administered by clinical route
o Parameters that should be monitored daily include

Answer 6

 Behavioural
 Physiological
 Biochemical
 Histological

Question 7

• Local toxicity studies - route of administration

Answer 7

o Dermal
o Rectal tolerance
o Parenteral drugs
* Allergenicity/Hypersensitivity toxicological studies
o Guinea pig maximization test
 Determination of maximum non-irritant or minimum irritant dose
o Local lymph node assay
* Carcinogenicity/Oncogenicity studies
o Life-time bioassays
o Drug used for >6 months or frequent intermittent use for chronic diseases
o Chemical structure of drug may indicate carcinogenic potential; this test confirms it
* Reproductive and developmental toxicity

Question 8

Therapeutic index

Answer 8

The ratio of the dose of the drug that produces an unwanted (toxic) effect to that producing a wanted (therapeutic) effect.
“LD50” /”ED50”