Many people agonize about the predictivity of the science of pharmacogenetics. Somehow there is an expectation that pharmacogenetics should somehow lead to position where we can stop thinking.
Sounds a bit harsh but true.
Pharmacogenetics began as a science to understand the genetic basis for outlier behaviour. In much earlier experiences, outliers were characterized principally by phenotypic behaviour. As it is now, phenotypes tended to be classified in binary fashion - rapid/slow, fast/slow, extensive/poor. Such binary depictions of reality can only be predictive when the reaction or process in point is singular, critical or both. In some situations drug response can be described binarily as 'at risk for toxicity', or 'not at risk', e.g. G6PD deficiencies or HLA B*1502 for carbamazepine-SJS. For the most part however, pharmacogenetics data only helped explain genetic bases for limited aspects of drug response.
FDA classification: +, for information only; ++, recommended; +++, required
Gervasini et al, Eur J Clin Pharmacol (2010) 66:755–774
In highly controlled experiments, it can be easily shown that genetic variants can result in either loss or gain in function in specific processes related to drug response, e.g. drug metabolism and clearances. However since drug response/metabolism/
pharmacokinetics is seldom the result of a singular process, genotyping a genetic variant almost never provides a clear prediction of what the final drug response would be like.
Unfortunately the market place has misled many to believe that we can somehow construct a genetic testing panel that will predict with some degree of finality, what the patient's drug response and hence his drug dosage requirements will be. Hooray.... and we can therefore stop thinking! This line of thinking is clearly fallacious. The concept of 'personalized medicine' has been hijacked (biotech commercialism?) to refer to a one step genotyping approach to therapeutics when correctly it should refer to the ability to look at the patient in totality, i.e. the entire person - not just from the perspective of his constitutive make-up, but the totality of contributions of his altered physiology and environmental effects.
The more correct and rational approach is that of 'optimization', but the term sadly is far more mundane and less commercially sexy compared to 'personalized medicine'.
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I agree with your general premise and that most negative drug interactions effects involve more than one gene.
ReplyDeleteHowever, the mere concept of genetic diversity is still in its infancy in the industry. Just getting the general pharma industry and the FDA et al to begin to understand and use an element of genetics in their testing is worthwhile goal.
It won’t mean ‘personalized medicine' as espoused by media day, or even tomorrow - but it’s a step towards the idea that diversity counts/exists, and can be part of the equation in drug testing and perhaps treatments in the future.
Michael V. Wiles (mvwiles@earthlink.net)
Absolutely. It is certainly a significant step getting industry to incorporate considerations of genetic diversity into their drug development. The unfortunate result may however be that since significant amounts have been invested into developing this line of development, genetic testing will increasingly be touted as *the* solution to therapeutic problems.
ReplyDeletePerhaps a more sensible approach might be the investment into developing good biomarkers of clinical drug response that will allow optimization of drug dosages.