D. A. Hesselink
Ann Transplant 2008; 13(1): 13-14
Immunosuppressive drug therapy in transplantation medicine is characterized and complicated by considerable toxicity of the individual agents used and large interindividual variability in drug pharmacokinetics. Many of the immunosuppressive drugs in use today are dosed according to blood concentrations because the correlation between their concentration and (clinical) effect is stronger than the relationship between dose and effect. This practice, known as therapeutic drug monitoring (TDM), has resulted in a more individualized immunosuppressive therapy but suffers from several drawbacks. Most importantly, it can only be performed after the start of drug treatment and therefore has limited predictive value and does not aid in determining the starting dose of an immunosuppressive agent for an individual patient. Pre-transplant assessment of immunosuppressive drug pharmacokinetics has not solved these difficulties as the correlation between pre- and posttransplant pharmacokinetic values in general is poor. In addition, TDM does not provide any mechanistic information on the factors that underlie a drug's pharmacokinetics. Not surprisingly, pharmacogenetics has created considerable enthusiasm in transplantation medicine as it has the potential to identify "the right drug and the right dose" for an individual patient. It has been hypothesized that by using genetic information, an individual's response to a particular immunosuppressive drug after transplantation may be predicted. The choice for a particular immunosuppressant and its (starting) dose could thus be guided by genetics. In the last decade, our understanding of the role of inheritance in interindividual variability in response to immunosuppressive drug therapy has increased enormously. Most of the pharmacogenetic studies performed to date have focused on the calcineurin inhibitors cyclosporine and tacrolimus. Both drugs are substrates of the multidrug-efï¬‚ux pump P-glycoprotein (P-gp), encoded by the ABCB1 gene in which several single-nucleotide polymorphisms (SNPs) have been identified. In addition, cyclosporine and tacrolimus are metabolized by the cytochrome P450 (CYP) iso-enzymes CYP3A4 and CYP3A5, which are also polymorphically expressed. For tacrolimus it has been demonstrated that patients expressing CYP3A5 require a tacrolimus dose that is between 50-70% higher compared with CYP3A5 nonexpressers. In line with these findings, patients expressing CYP3A5 were shown to have a lower exposure to tacrolimus in the early phase after transplantation. In addition, several SNPs in ABCB1 and CYP3A4 have been associated with tacrolimus dose requirement. However, the inï¬‚uence of genetic variation in ABCB1 on tacrolimus exposure appears smaller compared with CYP3A5, whereas the reported associations of tacrolimus dose requirement with CYP3A4 SNPs may have resulted from linkage with certain CYP3A5 genotypes. The results of studies investigating cyclosporine pharmacokinetics in relation to SNPs in CYP3A4, CYP3A5 and ABCB1 are conï¬‚icting. Many investigators have not identified any associations between SNPs in these genes and cyclosporine pharmacokinetics, whereas others have reported statistically significant associations. These contrasting results may have arisen through differences between studies with regard to, for example, patients studied, pharmacokinetic assessment, time after transplantation, ethnicity of the subjects investigated and co-medication used. Nonetheless, taken together, it appears that the effect of SNPs in CYP3A and ABCB1 on cyclosporine pharmacokinetics, if any, is small and at present unlikely to contribute to improved patient care. Polymorphisms in CYP3A and ABCB1 have also been investigated in relation to clinical outcomes after transplantation. From these studies, it appears that the higher tacrolimus dose requirement of patients expressing CYP3A5 and their delay in reaching tacrolimus target concentrations does not lead to a higher incidence of acute rejection. Also, CYP3A5 non-expressers do not appear to have a higher incidence of tacrolimus-related side effects. This observation is likely explained by the practice to perform rapid tacrolimus dose adjustments in the early phase after transplantation, thereby limiting differences in tacrolimus exposure between CYP3A5 expressers and non-expressers. By contrast, the ABCB1 genotype of the donor has been associated with calcineurin-inhibitor-related nephrotoxicity. Kidneys from donors homozygous for the ABCB1 3435T allele were shown to be more at risk for cyclosporine-related nephrotoxicity compared with kidneys from donors with the 3435CT or 3435CC genotype. CYP3A5 expression in the transplanted kidney has also been linked with the nephrotoxic effects of calcineurin inhibitors. In addition, ABCB1 and CYP3A5 genotype appear to be risk factors for the development of hypertension although it is not known whether this association also applies to calcineurin inhibitor-induced hypertension. At present only limited data exist on the inï¬‚uence of genetic variation on the pharmacokinetics and pharmacodynamics of other immunosuppressive agents. Several SNPs in the UGT1A9 and MRP2 genes have been associated with MPA exposure, whereas CYP3A5 genotype affects sirolimus pharmacokinetics. It is to be expected that the number of studies investigating the genetic basis of interindividual variability in MPA pharmacokinetics and clinical outcome will rapidly expand. In conclusion, pharmacogenetic research in transplantation medicine has identifi ed associations between several SNPs in candidate genes and immunosuppressive drug pharmacokinetics, and to a lesser extent, clinical outcomes. Hopefully, some of our current knowledge will translate into clinical practice in the next few years. At present it appears that CYP3A5 and ABCB1 are the most promising in this respect. As SNPs in these genes have been shown to be associated with tacrolimus exposure, genotyping patients before or shortly after transplantation may be of help to determine the tacrolimus starting dose. A prospective study investigating the efficacy of such a pharmacogenetics-assisted tacrolimus dosing strategy is currently underway. In this study, transplant patients are randomized to receive a standard tacrolimus starting dose or a dose based on an individual's CYP3A5 genotype. The association between ABCB1 and CYP3A5 genotype and calcineurin inhibitor-related nephrotoxicity may provide another means to improve transplantation outcomes. Patients at high risk for nephrotoxicity could be treated with a calcineurin inhibitor-free immunosuppressive drug regimen or be tapered off these agents early after transplantation. As such, pharmacogenetics may reduce late rather than early allograft loss. For other, less-well defined associations between certain polymorphisms, immunosuppressive drug pharmacokinetics and clinical outcomes, large prospective, observational studies or genetic meta-analysis may be of help. Ultimately, the pharmacogenetic profile of an individual transplant patient may assist clinicians when selecting an immunosuppressive drug regimen.
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