Pharmacogenetics and immunosuppressive drugs in solid organ transplantation

Nature Reviews Nephrology

Volumn 10, Issue 12, 2014, Pages 725-731

  Van Gelder, Teun ^a   Van Schaik, Ron H ^a   Hesselink, Dennis A ^a  

^a ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

AZATHIOPRINE; CYCLOSPORIN A; EVEROLIMUS; IMMUNOSUPPRESSIVE AGENT; MYCOPHENOLIC ACID; RAPAMYCIN; TACROLIMUS; CYCLOSPORIN; MYCOPHENOLATE MOFETIL;

CLINICAL PRACTICE; DRUG MONITORING; DRUG TRANSPORT; ELECTRONIC MEDICAL RECORD; GRAFT RECIPIENT; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; KIDNEY GRAFT REJECTION; KIDNEY TRANSPLANTATION; ORGAN TRANSPLANTATION; PHARMACOGENETICS; PRESCRIPTION; REVIEW; ADVERSE EFFECTS; ANALOGS AND DERIVATIVES; DRUG EFFECTS; EVIDENCE BASED MEDICINE; FEMALE; GENETIC POLYMORPHISM; GENETICS; GRAFT REJECTION; GRAFT SURVIVAL; HISTOCOMPATIBILITY; MALE; PREDICTIVE VALUE; PROCEDURES;

AZATHIOPRINE; CYCLOSPORINE; DRUG MONITORING; EVIDENCE-BASED MEDICINE; FEMALE; GRAFT REJECTION; GRAFT SURVIVAL; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KIDNEY TRANSPLANTATION; MALE; MYCOPHENOLIC ACID; ORGAN TRANSPLANTATION; PHARMACOGENETICS; POLYMORPHISM, GENETIC; PREDICTIVE VALUE OF TESTS; SIROLIMUS; TACROLIMUS; TRANSPLANTATION IMMUNOLOGY;

EID: 84911955819     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2014.172     Document Type: Review

References (98)

1. US Department of Health and Human Services. Table of pharmacogenomic biomarkers in drug labeling [online], http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm (2014).
2. Swen, J. J. et al. Pharmacogenetics: from bench to byte - An update of guidelines. Clin. Pharmacol. Ther. 89, 662-673 (2011).
3. Overby, C. L., Tarczy-Hornoch, P., Hoath, J. I., Kalet, I. J. & Veenstra, D. L. Feasibility of incorporating genomic knowledge into electronic medical records for pharmacogenomic clinical decision support. BMC Bioinformatics 11 (Suppl. 9), S10 (2010).
4. Birdwell, K. A. et al. The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients. Pharmacogenet. Genomics 22, 32-42 (2012).
5. PharmGKB. The Pharmacogenomics Knowledge Base [online], http://www.pharmgkb.org/(2014).
6. Thervet, E. et al. Long-term results of TPMT activity monitoring in azathioprine-treated renal allograft recipients. J. Am. Soc. Nephrol. 12, 170-176 (2001).
7. Evans, W. E. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther. Drug Monit. 26, 186-191 (2004).
8. Budhiraja, P. & Popovtzer, M. Azathioprine-related myelosuppression in a patient homozygous for TPMT∗3A. Nat. Rev. Nephrol. 7, 478-484 (2011).
9. Schaeffeler, E. et al. Highly multiplexed genotyping of thiopurine s-methyltransferase variants using MALD-TOF mass spectrometry: reliable genotyping in different ethnic groups. Clin. Chem. 54, 1637-1647 (2008).
10. Thompson, A. J. et al. The cost-effectiveness of a pharmacogenetic test: a trial-based evaluation of TPMT genotyping for azathioprine. Value Health 17, 22-33 (2014).
11. Kurzawski, M., Dziewanowski, K., Gawrońska-Szklarz, B., Domański, L. &, Droździk, M. The impact of thiopurine s-methyltransferase polymorphism on azathioprine-induced myelotoxicity in renal transplant recipients. Ther. Drug Monit. 27, 435-441 (2005).
12. Relling, M. V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin. Pharmacol. Ther. 89, 387-391 (2011).
13. Relling, M. V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin. Pharmacol. Ther. 93, 324-325 (2013).
14. Derijks, L. J. & Hommes, D. W. Thiopurines in inflammatory bowel disease: new strategies for optimization of pharmacotherapy? Curr. Gastroenterol. Rep. 8, 89-92 (2006).
15. Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients 2010 Data Report. Am. J. Transplant. 12 (Suppl. 1), 1-156 (2012).
16. van Gelder, T. Therapeutic drug monitoring for mycophenolic acid is value for (little) money. Clin. Pharmacol. Ther. 90, 203-204 (2011).
17. Hesselink, D. A. & van Gelder, T. Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin. Pharmacol. Ther. 78, 317-321 (2005).
18. Kuypers, D. R., Naesens, M., Vermeire, S. & Vanrenterghem, Y. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin. Pharmacol. Ther. 78, 351-361 (2005).
19. Fukuda, T. et al. UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients. Ther. Drug Monit. 34, 671-679 (2012).
20. van Schaik, R. H. et al. UGT1A9 275T>A/2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients. Clin. Pharmacol. Ther. 86, 319-327 (2009).
21. Sánchez-Fructuoso, A. I. et al. The prevalence of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T and its influence on mycophenolic acid pharmacokinetics in stable renal transplant patients. Transplant. Proc. 41, 2313-2316 (2009).
22. Baldelli, S. et al. C-440T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics 8, 1127-1141 (2007).
23. Guo, D. et al. Polymorphisms of UGT1A9 and UGT2B7 influence the pharmacokinetics of mycophenolic acid after a single oral dose in healthy Chinese volunteers. Eur. J. Clin. Pharmacol. 69, 843-849 (2013).
24. Lloberas, N. et al. Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients-results of the Pharmacogenomic Substudy within the Symphony Study. Nephrol. Dial. Transplant. 26, 3784-3793 (2011).
25. Picard, N. et al. The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clin. Pharmacol. Ther. 87, 100-108 (2010).
26. Bouamar, R. et al. Mycophenolic acid-related diarrhea is not associated with polymorphisms in SLCO1B nor with ABCB1 in renal transplant recipients. Pharmacogenet. Genomics 22, 399-407 (2012).
27. Jacobson, P. A. et al. Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation. Transplantation 91, 309-316 (2011).
28. Woillard, J. B. et al. Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8∗2 variant allele. Br. J. Clin. Pharmacol. 69, 675-683 (2010).
29. van Agteren, M. et al. AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism. Ther. Drug Monit. 30, 439-444 (2008).
30. Prausa, S. E. et al. UGT genotype may contribute to adverse events following medication with mycophenolate mofetil in pediatric kidney transplant recipients. Clin. Pharmacol. Ther. 85, 495-500 (2009).
31. Barraclough, K. A., Lee, K. J. & Staatz, C. E. Pharmacogenetic influences on mycophenolate therapy. Pharmacogenomics 11, 369-390 (2010).
32. Natsumeda, Y. et al. Two distinct cDNAs for human IMP dehydrogenase. J. Biol. Chem. 265, 5292-5295 (1990).
33. Weimert, N. A., Derotte, M., Alloway, R. R., Woodle, E. S. & Vinks, A. A. Monitoring of inosine monophosphate dehydrogenase activity as a biomarker for mycophenolic acid effect: potential clinical implications. Ther. Drug Monit. 29, 141-149 (2007).
34. Glander, P. et al. Non-radioactive determination of inosine 5'-monophosphate dehydro-genase (IMPDH) in peripheral mononuclear cells. Clin. Biochem. 34, 543-549 (2001).
35. Glander, P. et al. Improved assay for the nonradioactive determination of inosine 5'-monophosphate dehydrogenase activity in peripheral blood mononuclear cells. Ther. Drug Monit. 31, 351-359 (2009).
36. Vethe, N. T. & Bergan, S. Determination of inosine monophosphate dehydrogenase activity in human CD4+ cells isolated from whole blood during mycophenolic acid therapy. Ther. Drug Monit. 28, 608-613 (2006).
37. Vethe, N. T., Bremer, S., Rootwelt, H. & Bergan, S. Pharmacodynamics of mycophenolic acid in CD4+ cells: a single-dose study of IMPDH and purine nucleotide responses in healthy individuals. Ther. Drug Monit. 30, 647-655 (2008).
38. Budde, K. et al. Pharmacodynamic monitoring of mycophenolate mofetil. Clin. Chem. Lab. Med. 38, 1213-1216 (2000).
39. Glander, P. et al. Pre-transplant inosine monophosphate dehydrogenase activity is associated with clinical outcome after renal transplantation. Am. J. Transplant. 4, 2045-2051 (2004).
40. Glander, P., Hambach, P., Liefeldt, L. & Budde, K. Inosine 5'-monophosphate dehydrogenase activity as a biomarker in the field of transplantation. Clin. Chim. Acta 413, 1391-1397 (2012).
41. Glander, P. & Budde, K. Target enzyme activity as a biomarker for immunosuppression. Ther. Drug Monit. 32, 257-260 (2010).
42. Sombogaard, F. et al. Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T>C polymorphism. Pharmacogenet. Genomics 19, 626-634 (2009).
43. Wang, J. et al. IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients. Clin. Pharmacol. Ther. 83, 711-717 (2008).
44. Ohmann, E. L. et al. Genetic polymorphisms influence mycophenolate mofetil-related adverse events in pediatric heart transplant patients. J. Heart Lung Transplant. 29, 509-516 (2010).
45. Molinaro, M. et al. Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients. Drug Metab. Pharmacokinet. 28, 109-117 (2013).
46. Shah, S., Harwood, S. M., Döhler, B., Opelz, G. & Yaqoob, M. M. Inosine monophosphate dehydrogenase polymorphisms and renal allograft outcome. Transplantation 94, 486-491 (2012).
47. Dunn, C. J., Wagstaff, A. J., Perry, C. M., Plosker, G. L. & Goa, K. L. Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ transplantation. Drugs 61, 1957-2016 (2001).
48. Morris, R. G. et al. Comparison of trough, 2-hour, and limited AUC blood sampling for monitoring cyclosporin (Neoral) at day 7 post-renal transplantation and incidence of rejection in the first month. Ther. Drug Monit. 24, 479-486 (2002).
49. Mahalati, K. et al. Approaching the therapeutic window for cyclosporine in kidney transplantation: a prospective study. J. Am. Soc. Nephrol. 12, 828-833 (2001).
50. Knight, S. R. & Morris, P. J. The clinical benefits of cyclosporine C2-level monitoring: a systematic review. Transplantation 83, 1525-1535 (2007).
51. Hesselink, D. A., van Gelder, T. & van Schaik, R. H. The pharmacogenetics of calcineurin inhibitors: one step closer toward individualized immunosuppression? Pharmacogenomics 6, 323-337 (2005).
52. Bouamar, R. et al. Polymorphisms in CYP3A5, CYP3A4, and ABCB1 are not associated with cyclosporine pharmacokinetics nor with cyclosporine clinical end points after renal transplantation. Ther. Drug Monit. 33, 178-184 (2011).
53. Staatz, C. E., Goodman, L. K. & Tett, S. E. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin. Pharmacokinet. 49, 141-175 (2010).
54. Anglicheau, D. et al. Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction. Kidney Int. 70, 1019-1025 (2006).
55. Hesselink, D. A., Bouamar, R. & van Gelder, T. The pharmacogenetics of calcineurin inhibitor-related nephrotoxicity. Ther. Drug Monit. 32, 387-393 (2010).
56. Koziolek, M. J., Riess, R., Geiger, H., Thévenod, F. & Hauser, I. A. Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients. Kidney Int. 60, 156-166 (2001).
57. Hauser, I. A. et al. ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. J. Am. Soc. Nephrol. 16, 1501-1511 (2005).
58. Cattaneo, D. et al. ABCB1 genotypes predict cyclosporine-related adverse events and kidney allograft outcome. J. Am. Soc. Nephrol. 20, 1404-1415 (2009).
59. Woillard, J. B. et al. Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up. Clin. Pharmacol. Ther. 88, 95-100 (2010).
60. De Meyer, M. et al. Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation. J. Surg. Res. 178, 988-995 (2012).
61. Moore, J. et al. Donor ABCB1 variant associates with increased risk for kidney allograft failure. J. Am. Soc. Nephrol. 23, 1891-1899 (2012).
62. Jacobson, P. A. et al. Genetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity: results from a kidney transplant consortium. Transplantation 93, 624-631 (2012).
63. Llaudó, I. et al. Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the Pharmacogenomic Substudy within the Symphony Study. Transpl. Int. 26, 177-186 (2013).
64. Crettol, S. et al. Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients. Pharmacogenet. Genomics 18, 307-315 (2008).
65. Falck, P. et al. Declining intracellular Tlymphocyte concentration of cyclosporine A precedes acute rejection in kidney transplant recipients. Transplantation 85, 179-184 (2008).
66. Wallemacq, P. et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther. Drug Monit. 31, 139-152 (2009).
67. Macphee, I. A. et al. Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 74, 1486-1489 (2002).
68. Thervet, E. et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 76, 1233-1235 (2003).
69. Haufroid, V. et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics 14, 147-154 (2004).
70. Jacobson, P. A. et al. Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation 91, 300-308 (2011).
71. Zhao, W. et al. Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients. Eur. J. Clin. Pharmacol. 69, 189-195 (2013).
72. Wehland, M. et al. Differential impact of the CYP3A5∗1 and CYP3A5∗3 alleles on pre-dose concentrations of two tacrolimus formulations. Pharmacogenet. Genomics 21, 179-184 (2011).
73. Hesselink, D. A., Bouamar, R., Elens, L., van Schaik, R. H. & van Gelder, T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin. Pharmacokinet. 53, 123-139 (2014).
74. Barry, A. & Levine, M. A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients. Ther. Drug Monit. 32, 708-714 (2010).
75. MacPhee, I. A. et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am. J. Transplant. 4, 914-919 (2004).
76. Haufroid, V. et al. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. Am. J. Transplant. 6, 2706-2713 (2006).
77. MacPhee, I. A. & Holt, D. W. A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype. Transplantation 85, 163-165 (2008).
78. Thervet, E. et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin. Pharmacol. Ther. 87, 721-726 (2010).
79. van Gelder, T., van Schaik, R. H. & Hesselink, D. A. Practicability of pharmacogenetics in transplantation medicine. Clin. Pharmacol. Ther. 95, 262-264 (2014).
80. Wang, D., Guo, Y., Wrighton, S. A., Cooke, G. E. & Sadee, W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 11, 274-286 (2011).
81. Elens, L. et al. A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients. Clin. Chem. 57, 1574-1583 (2011).
82. Elens, L. et al. Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics 12, 1383-1396 (2011).
83. Passey, C. et al. Dosing equation for tacrolimus using genetic variants and clinical factors. Br. J. Clin. Pharmacol. 72, 948-957 (2011).
84. Passey, C. et al. Validation of tacrolimus equation to predict troughs using genetic and clinical factors. Pharmacogenomics 13, 1141-1147 (2012).
85. Elens, L., Hesselink, D. A., van Schaik, R. H. & van Gelder, T. The CYP3A4∗22 allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations. Br. J. Clin. Pharmacol. 75, 1545-1547 (2013).
86. Hesselink, D. A. et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin. Pharmacol. Ther. 74, 245-254 (2003).
87. Le Meur, Y. et al. CYP3A5∗3 influences sirolimus oral clearance in de novo and stable renal transplant recipients. Clin. Pharmacol. Ther. 80, 51-60 (2006).
88. Miao, L. Y., Huang, C. R., Hou, J. Q. & Qian, M. Y. Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients. Biopharm. Drug Dispos. 29, 1-5 (2008).
89. Anglicheau, D. et al. Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy. Am. J. Transplant. 5, 595-603 (2005).
90. Woillard, J. B. et al. Effect of CYP3A4∗22, POR∗28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients. Clin. Chem. 59, 1761-1769 (2013).
91. Sam, W. J. et al. Associations of ABCB1 3435C>T and IL-10-1082G>A polymorphisms with long-term sirolimus dose requirements in renal transplant patients. Transplantation 92, 1342-1347 (2011).
92. Gorski, J. C. et al. In vivo effects of interleukin-10 on human cytochrome P450 activity. Clin. Pharmacol. Ther. 67, 32-43 (2000).
93. Woillard, J. B. et al. Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients. Pharmacogenet. Genomics 22, 725-732 (2012).
94. Picard, N., Rouguieg-Malki, K., Kamar, N., Rostaing, L. & Marquet, P. CYP3A5 genotype does not influence everolimus in vitro metabolism and clinical pharmacokinetics in renal transplant recipients. Transplantation 91, 652-656 (2011).
95. Kniepeiss, D. et al. The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation. Clin. Transplant. 25, 146-150 (2011).
96. Schoeppler, K. E., Aquilante, C. L., Kiser, T. H., Fish, D. N. & Zamora, M. R. The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients. Clin. Transplant. 28, 590-597 (2014).
97. Moes, D. J. et al. Population pharmacokinetics and pharmacogenetics of everolimus in renal transplant patients. Clin. Pharmacokinet. 51, 467-480 (2012).
98. Bell, G. C. et al. Development and use of active clinical decision support for preemptive pharmacogenomics. J. Am. Med. Inform. Assoc. 21, e93-e99 (2014).