Influence of genetic polymorphisms of CYP3A5 and ABCB1 on sirolimus pharmacokinetics, patient and graft survival and other clinical outcomes in renal transplant
-
Consuelo Rodríguez-Jiménez
,
Mar García-Saiz
Abstract
Background:
In transplant patients receiving de novo anticalcineurin-free sirolimus (SRL)-based immunosuppression, we determined the influence of cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette, sub-family B (MDR/TAP), member (ABCB1) genotypes on SRL blood levels and medium-term relevant clinical outcomes, in order to improve effectiveness of immunosuppression strategies when anti-mammalian target of rapamycin (anti-mTOR) inhibitor is indicated for clinical reasons.
Methods:
Forty-eight renal transplant recipients (suffered 48% diabetes mellitus, 91% hypertension, and 47% dyslipidemia) were genotyped for CYP3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Sirolimus blood levels were determined using microparticle enzyme immunoassay technique. Relationships between genotypes and pharmacokinetics, graft function, and patient-graft survival were determined by univariate analysis.
Results:
CYP3A5*1/*3 showed lower SRL levels than CYP3A5*3/*3 (4.13±1.54 vs. 8.49±4.18 ng/mL; p=0.003) and level/dose ratio (LDR) (92.74±37.47 vs. 178.62±116.45; p=0.019) in early post-transplant period. In ABCB1 polymorphisms, CT genotypes showed higher SRL levels than CC and TT (8.93±2.22 vs. 7.28±2.47 vs. 7.35±1.15 ng/mL; p=0.038) in the late period; LDR in CC and CT were 171.29±36.24 vs. 335.66±138.71 (p=0.003), despite receiving lower doses (p=0.018). Acute rejection rate was 14% vs. 42% for *3/*3 and 14% (TT), 48% (CT), and 31% (CC). Median patient survival was 45 months, significantly lower than that of *3/*3 patients (69 months). Death-censored graft survival during 5-year follow-up was similar for both CYP3A5 genotypes and significantly lower in TT than CT and CC groups, without survival differences.
Conclusions:
CYP3A5 and ABCB1 polymorphisms influenced SRL levels; preliminary data suggest this may affect patient and graft survival. Genotyping renal transplant patients could help select candidates for SRL (genotype*3/*3 for CYP3A5 and CT for ABCB1), when anti-mTOR immunosuppression is indicated.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Programa canario de promoción de Redes de Investigación en Biomedicina y Ciencias de la Salud (InRedCan) y del Programa para la creación de Grupos de Investigación Emergentes; Fundación Canaria de Investigación y Salud (FUNCIS), (Grant/Award Number: ‘PI32/06’).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Hernández D, Moreso F. Has patient survival following renal transplantation improved in the era of modern immunosuppression? Nefrologia 2013;33:171–80.Suche in Google Scholar
2. Ponticelli C. Present and future of immunosuppressive therapy in kidney transplantation. Transplant Proc 2011;43:2439–40.10.1016/j.transproceed.2011.06.025Suche in Google Scholar PubMed
3. Moes DJ, Guchelaar HJ, de Fijter JW. Sirolimus and everolimus in kidney transplantation. Drug Discov Today 2015;20:1243–9.10.1016/j.drudis.2015.05.006Suche in Google Scholar PubMed
4. Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet 2001;40:573–85.10.2165/00003088-200140080-00002Suche in Google Scholar PubMed
5. Stenton SB, Partovi N, Ensom MH. Sirolimus: the evidence for clinical pharmacokinetic monitoring. Clin Pharmacokinet 2005;44:769–86.10.2165/00003088-200544080-00001Suche in Google Scholar PubMed
6. Mourad M, Mourad G, Wallemacq P, Garrigue V, Van BC, Van K, V, et al. Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. Transplantation 2005;80:977–84.10.1097/01.TP.0000174131.47469.D2Suche in Google Scholar
7. Miao LY, Huang CR, Hou JQ, Qian MY. Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients. Biopharm Drug Dispos 2008;29:1–5.10.1002/bdd.577Suche in Google Scholar PubMed
8. Renders L, Frisman M, Ufer M, Mosyagin I, Haenisch S, Ott U, et al. CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients. Clin Pharmacol Ther 2007;81:228–34.10.1038/sj.clpt.6100039Suche in Google Scholar PubMed
9. Lee J, Huang H, Chen Y, Lu X. ABCB1 haplotype influences the sirolimus dose requirements in Chinese renal transplant recipients. Biopharm Drug Dispos 2014;35:164–72.10.1002/bdd.1881Suche in Google Scholar PubMed
10. Zochowska D, Wyzgal J, Paczek L. Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients. Ann Transplant 2012;17:36–44.10.12659/AOT.883456Suche in Google Scholar PubMed
11. Lukas JC, Calvo R, Zografidis A, Ortega I, Suarez E. Simulation of sirolimus exposures and population variability immediately post renal transplantation: importance of the patient’s CYP3A5 genotype in tailoring treatment. Biopharm Drug Dispos 2010;31:129–37.10.1002/bdd.697Suche in Google Scholar PubMed
12. Anglicheau D, Le CD, Lechaton S, Laurent-Puig P, Kreis H, Beaune P, et al. Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy. Am J Transplant 2005;5:595–603.10.1111/j.1600-6143.2005.00745.xSuche in Google Scholar PubMed
13. Sam WJ, Chamberlain CE, Lee SJ, Goldstein JA, Hale DA, Mannon RB, et al. Associations of ABCB1 3435C>T and IL-10-1082G>A polymorphisms with long-term sirolimus dose requirements in renal transplant patients. Transplantation 2011;92:1342–7.10.1097/TP.0b013e3182384ae2Suche in Google Scholar PubMed PubMed Central
14. Attia J, Ioannidis JP, Thakkinstian A, McEvoy M, Scott RJ, Minelli C, et al. How to use an article about genetic association: B: are the results of the study valid? J Am Med Assoc 2009;301:191–7.10.1001/jama.2008.946Suche in Google Scholar PubMed
15. Montoya-Delgado LE, Irony TZ, de BPC, Whittle MR. An unconditional exact test for the Hardy-Weinberg equilibrium law: sample-space ordering using the Bayes factor. Genetics 2001;158:875–83.10.1093/genetics/158.2.875Suche in Google Scholar PubMed PubMed Central
16. Hardy Weinberg Calculator. Available at: http://emerald.tufts.edu/~mcourt01/Documents/Court%20lab%20-%20HW%20calculator.xls. Accessed: 2 Sep 2015.Suche in Google Scholar
17. Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036–42.10.1097/00007890-199904150-00017Suche in Google Scholar PubMed
18. Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000;69:1252–60.10.1097/00007890-200004150-00009Suche in Google Scholar PubMed
19. Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 2002;74:1070–6.10.1097/00007890-200210270-00002Suche in Google Scholar PubMed
20. Flechner SM, Kurian SM, Solez K, Cook DJ, Burke JT, Rollin H, et al. De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant 2004;4:1776–85.10.1111/j.1600-6143.2004.00627.xSuche in Google Scholar PubMed
21. Hamdy AF, El-Agroudy AE, Bakr MA, Mostafa A, El-Baz M, El-Shahawy E, et al. Comparison of sirolimus with low-dose tacrolimus versus sirolimus-based calcineurin inhibitor-free regimen in live donor renal transplantation. Am J Transplant 2005;5:2531–8.10.1111/j.1600-6143.2005.01064.xSuche in Google Scholar PubMed
22. Hamdy AF, Bakr MA, Ghoneim MA. Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients. J Am Soc Nephrol 2008;19:1225–32.10.1681/ASN.2007091001Suche in Google Scholar PubMed PubMed Central
23. Larson TS, Dean PG, Stegall MD, Griffin MD, Textor SC, Schwab TR, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 2006;6:514–22.10.1111/j.1600-6143.2005.01177.xSuche in Google Scholar
24. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562–75.10.1056/NEJMoa067411Suche in Google Scholar
25. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9:S1–155.10.1111/j.1600-6143.2009.02834.xSuche in Google Scholar
26. Lim WH, Eris J, Kanellis J, Pussell B, Wiid Z, Witcombe D, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant 2014;14:2106–19.10.1111/ajt.12795Suche in Google Scholar
27. Sawinski D, Trofe-Clark J, Leas B, Uhl S, Tuteja S, Kaczmarek JL, et al. Calcineurin inhibitor minimization, conversion, withdrawal, and avoidance strategies in renal transplantation: a systematic review and meta-analysis. Am J Transplant 2016;16:2117–38.10.1111/ajt.13710Suche in Google Scholar
28. Tedesco-Silva H, Peddi VR, Sánchez-Fructuoso A, Marder BA, Russ GR, Diekmann F, et al. Open-label, randomized study of transition from tacrolimus to sirolimus immunosuppression in renal allograft recipients. Transplant Direct 2016;2:e69.10.1097/TXD.0000000000000579Suche in Google Scholar
29. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003;74:245–54.10.1016/S0009-9236(03)00168-1Suche in Google Scholar
30. Akbas SH, Bilgen T, Keser I, Tuncer M, Yucetin L, Tosun O, et al. The effect of MDR1 (ABCB1) polymorphism on the pharmacokinetic of tacrolimus in Turkish renal transplant recipients. Transplant Proc 2006;38:1290–2.10.1016/j.transproceed.2006.02.079Suche in Google Scholar PubMed
31. Sam WJ, Chamberlain CE, Lee SJ, Goldstein JA, Hale DA, Mannon RB, et al. Associations of ABCB1 and IL-10 genetic polymorphisms with sirolimus-induced dyslipidemia in renal transplant recipients. Transplantation 2012;94:971–7.10.1097/TP.0b013e31826b55e2Suche in Google Scholar PubMed PubMed Central
32. Palepu S, Prasad GV. New-onset diabetes mellitus after kidney transplantation: current status and future directions. World J Diabetes 2015;6:445–55.10.4239/wjd.v6.i3.445Suche in Google Scholar PubMed PubMed Central
33. Barlow AD, Nicholson ML, Herbert TP. Evidence for rapamycin toxicity in pancreatic beta-cells and a review of the underlying molecular mechanisms. Diabetes 2013;62:2674–82.10.2337/db13-0106Suche in Google Scholar PubMed PubMed Central
34. Gervasini G, Vizcaino S, Gasiba C, Carrillo JA, Benitez J. Differences in CYP3A5*3 genotype distribution and combinations with other polymorphisms between Spaniards and other Caucasian populations. Ther Drug Monit 2005;27:819–21.10.1097/01.ftd.0000186914.32038.a0Suche in Google Scholar PubMed
35. Sinues B, Vicente J, Fanlo A, Vasquez P, Medina JC, Mayayo E, et al. CYP3A5*3 and CYP3A4*1B allele distribution and genotype combinations: differences between Spaniards and Central Americans. Ther Drug Monit 2007;29:412–6.10.1097/FTD.0b013e31811f390aSuche in Google Scholar PubMed
36. Bernal ML, Sinues B, Fanlo A, Mayayo E. Frequency distribution of C3435T mutation in exon 26 of the MDR1 gene in a Spanish population. Ther Drug Monit 2003;25:107–11.10.1097/00007691-200302000-00016Suche in Google Scholar PubMed
37. Boso V, Herrero MJ, Buso E, Galan J, Almenar L, Sanchez-Lazaro I, et al. Genotype and allele frequencies of drug-metabolizing enzymes and drug transporter genes affecting immunosuppressants in the Spanish white population. Ther Drug Monit 2014;36:159–68.10.1097/FTD.0b013e3182a94e65Suche in Google Scholar PubMed
38. Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies A. Impact of genetic polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on drug disposition and potential clinical implications: update of the literature. Clin Pharmacokinet 2015;54:709–35.10.1007/s40262-015-0267-1Suche in Google Scholar PubMed
39. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001;69:169–74.10.1067/mcp.2001.114164Suche in Google Scholar PubMed
40. Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 2012;27:9–54.10.2133/dmpk.DMPK-11-RV-111Suche in Google Scholar PubMed
41. Dally H, Bartsch H, Jager B, Edler L, Schmezer P, Spiegelhalder B, et al. Genotype relationships in the CYP3A locus in Caucasians. Cancer Lett 2004;207:95–9.10.1016/j.canlet.2003.12.011Suche in Google Scholar PubMed
42. Cusinato DA, Lacchini R, Romao EA, Moysés-Neto M, Coelho EB. Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients. Br J Clin Pharmacol 2014;78:364–72.10.1111/bcp.12345Suche in Google Scholar PubMed PubMed Central
©2017 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Review
- Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene
- Population Pharmacogenomics
- Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Croatian population
- Original Articles
- Role of treatment-modifying MTHFR677C>T and 1298A>C polymorphisms in metformin-treated Puerto Rican patients with type-2 diabetes mellitus and peripheral neuropathy
- Genotyping CYP2D6 by three different methods: advantages and disadvantages
- Relationship between metabolic phenotypes and genotypes of CYP1A2 and CYP2A6 in the Nigerian population
- Influence of genetic polymorphisms of CYP3A5 and ABCB1 on sirolimus pharmacokinetics, patient and graft survival and other clinical outcomes in renal transplant
- Cytotoxicity and cytochrome P450 inhibitory activities of Clinacanthus nutans
- Verification of propofol sulfate as a further human propofol metabolite using LC-ESI-QQQ-MS and LC-ESI-QTOF-MS analysis
Artikel in diesem Heft
- Frontmatter
- Review
- Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene
- Population Pharmacogenomics
- Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Croatian population
- Original Articles
- Role of treatment-modifying MTHFR677C>T and 1298A>C polymorphisms in metformin-treated Puerto Rican patients with type-2 diabetes mellitus and peripheral neuropathy
- Genotyping CYP2D6 by three different methods: advantages and disadvantages
- Relationship between metabolic phenotypes and genotypes of CYP1A2 and CYP2A6 in the Nigerian population
- Influence of genetic polymorphisms of CYP3A5 and ABCB1 on sirolimus pharmacokinetics, patient and graft survival and other clinical outcomes in renal transplant
- Cytotoxicity and cytochrome P450 inhibitory activities of Clinacanthus nutans
- Verification of propofol sulfate as a further human propofol metabolite using LC-ESI-QQQ-MS and LC-ESI-QTOF-MS analysis
