2013 - International Conference on Transplantomics and Biomarkers in Organ Transplantation

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Plenary 5: Complications

6.3 - Potential for pharmacogenetics to guide immunisuppresive therapy

Presenter: Iain, MacPhee, , United Kingdom
Authors: Iain MacPhee

Gene based drug monitoring

Development of pharmacogenetic strategies based on genetic variation in drug transporters, metabolic enzymes and drug targets has the potential to allow individualization of immunosuppressive drug prescribing.

The immunosuppressive drugs have a narrow therapeutic index, with wide variation in the blood concentration achieved from a given dose observed between individuals. This issue has been addressed through the use of therapeutic drug monitoring (TDM), but it may take 5 to 7 days to reach target blood concentrations using this approach. Data suggest that genetic prediction of the optimal initial drug dose can be complementary to TDM in achieving target blood concentrations quickly. The pharmacogenetic strategy that is closest to translation into clinical practice is the use of the cytochrome P450 (CYP) 3A5 genotype to predict the optimal initial dose for tacrolimus. However, this single genotype may not be sufficiently predictive to be clinically useful and an algorithm involving multiple genotypes including ABCB1, CYP3A4*22 and POR*28 and demographic factors may provide a better prediction. Genetic prediction of the optimal dose may be particularly useful for drugs with a long half-life, such as sirolimus, which require several days to achieve a steady state following the implementation of a change in drug dosing, resulting in a long response-time for TDM. The influence of genetic factors on intracellular drug concentrations and the consequences for efficacy and toxicity are an emerging area of research. The SNPs described in this process could be added to existing molecular tissue typing methodology at minimal extra financial expense.

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