Pharmacogenetic Biomarkers Predictive of the Pharmacokinetics and Pharmacodynamics of Immunosuppressive Drugs.

Picard, Nicolas Bergan, Stein Marquet, Pierre van Gelder, Teun Wallemacq, Pierre [UCL] Hesselink, Dennis A Haufroid, Vincent [UCL] et al.[show all]

In association with therapeutic drug monitoring of immunosuppressive drugs, pharmacogenetics has rapidly emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. Pharmacogenetic biomarkers are now readily available in most transplantation centers, at a limited cost and within a limited analytical time frame, which make them compatible with the clinical decision process. However, despite some evidence of clear associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several immunosuppressive drugs, pre-emptive genotyping and selection of the optimal starting dose based on the genetic background of the patient is still rarely performed in clinical practice. The main reason is probably the lack of formal proof that clinical outcome really improves after genotype-based dosing. So far, the only clinical recommendation in relation to pharmacogenetic biomarkers should be a doubling of the starting tacrolimus dose in patients who are CYP3A5 expressers, and even in this case, some authors still do not recommend pre-emptive genotyping but only genotype-based adaptation if the CYP3A5 genotype is already known. However, with the rise of new technologies, as next generation sequencing, allowing to obtain pre-emptive genetic information, one must be aware that the question will no longer be whether to genotype or not but rather whether or not to use the information already there. There was therefore a need to update the information available in relation to pharmacogenetic biomarkers for calcineurin inhibitors, mycophenolic acid, and mammalian target of rapamycin inhibitors.