Pharmacogenomics


     Pharmacogenomics is the study of gene variations (polymorphisms) and how they affect drug response.
     This term is often confused with the older term (used for the past 40 years) "pharmacogenetics" since both terms are used interchangeably.
     Pharmacogenetics refers to the relationship between genetic variability and the metabolism of drugs whereas pharmacogenomics expands this concept to include the drug efficacy (effectiveness) and toxicity and to determine different genetic targets for drug action.

     Pharmacogenomics is a modernisation of the standard drug research system. The testing system of a drug involves four stages of clinical trials:

Preclinical testing - the drug is analysed using:
   A. In vitro (in a petri dish in the lab) studies
   B. Isolated organs
   C. Animals (check for overdosing, effects on reproduction, cancer-causing properties etc.)

If the drug passes all of the testing at the preclinical stage, then the real clinical trials in people are undertaken...

Phase I Studies - uses both normal individuals and mildly symptomatic individuals to test:
   A. Safety, tolerability and how the drug is metabolised are the main goals of this stage.
   B. Single dose effects and then multiple dose effects.
   C. Efficacy (how effective the drug is) is also tested in the affected individuals.

Phase II Studies - uses individuals with disease symptoms in order to:
   A. Establish efficacy.
   B. Determine the optimal dose for Phase III studies.
The design of phase II studies generally involve only short-term exposure (e.g., 6 weeks) until there is sufficient evidence of efficacy to justify long-term exposure.

Phase III Studies - together with the phase II studies, aim to give sufficient evidence to gain approval from the FDA (Food and Drug Administration in the USA, or equivalent authorities in other countries). They do this by:
   A. Obtaining supportive data for long-term maintenance efficacy (e.g., 1 year)
   B. Increasing the range of the human subjects in terms of numbers of patients and patient years.
These studies are double-blind (where both subject and the individuals directly giving the drug to the subjects do not know if they are in a study), large-scale, placebo (some subjects are given an inactive fake drug so that they believe that they are receiving the drug) or active controlled, short- and long-term (e.g., 6 weeks followed by 1 year extension protocols).

Phase IV Studies - these are usually to support the marketing campaign of the drug, where the studies are generally carried out in the same target population as the original studies.
Once this is successful, then the drug can be fully marketed and released to the public.

     Pharmacogenomics in the wake of the HGP has greatly improved in this, now dated, approach in clinical trials research area. The length and cost of clinical trials can now be greatly lowered due to increased specificity of the target information. In phase I studies, screening individuals can help determine the influence of the variations on the pharmacokinetics (effects on the body over time) of the drug and in phase III studies, screening will reduce the risk (and cost) of this stage by targeting the specific genetic population group capable of responding correctly to the drug in question, providing a greater degree of success since different ethnic groups respond differently to particular drugs. The new pharmacogenomics also allows previously failed drug candidates to be revived, as they can now potentially be matched with an ideally responsive population.

     Determining new targets for new drugs in disease is crucial in improving the pharmaceutical industry: it is estimated that out of about 30,000 genes in the human genome, only a small number turn out to be suitable drug targets. With the HGP, we can now use about 3000 - 10,000 genes as targets for drugs since these genes produce the appropriate proteins for the drug to act on.

     Aside from improving drug targeting in terms of choosing the individuals for the drug, it can be seen that in the future choosing the drug for the individual will also be possible. This tailoring of drugs to suit individuals genetic response differences is ideal for eliminating the cases of hyper-responsive (over-reactive) and hypo-responsive (under-reactive) individuals. It can be fatal to be hyper-responsive (due to overdosing) but it is equally serious to be hypo-responsive and continue having disease symptoms even if reduced in frequency somewhat (e.g. epilepsy).
     However, genetic variations are not the sole contributor to variable drug responses; other variables such as health, diet, lifestyle (e.g. smoking) and drug combinations must certainly be taken into consideration, therefore although the genotype plays a large role in drug therapy, environmental factors need to be added to the equation.

 

Go to the Links & References page for further reading on this area.