Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation

Overview

Journal J Clin Med

Specialty General Medicine

Date 2023 Jul 14

PMID 37445489

Authors

Stefano Turolo

Alberto Edefonti

Marie Luise Syren

Giovanni Montini

Affiliations

Soon will be listed here.

Abstract

Kidney transplantation is the preferred therapeutic option for end-stage kidney disease, but, despite major therapeutic advancements, allograft rejection continues to endanger graft survival. Every patient is unique due to his or her clinical history, drug metabolism, genetic background, and epigenetics. For this reason, examples of "personalized medicine" and "precision medicine" have steadily increased in recent decades. The final target of precision medicine is to maximize drug efficacy and minimize toxicity for each individual patient. Immunosuppressive drugs, in the setting of kidney transplantation, require a precise dosage to avoid either adverse events (overdosage) or a lack of efficacy (underdosage). In this review, we will explore the knowledge regarding the pharmacogenomics of the main immunosuppressive medications currently utilized in kidney transplantation. We will focus on clinically relevant pharmacogenomic data, that is, the polymorphisms of the genes that metabolize immunosuppressive drugs.

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References

Alangari A . Genomic and non-genomic actions of glucocorticoids in asthma. Ann Thorac Med. 2010; 5(3):133-9. PMC: 2930650. DOI: 10.4103/1817-1737.65040. View

Aouam K, Kolsi A, Kerkeni E, Ben Fredj N, Chaabane A, Monastiri K . Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase. Pharmacogenomics. 2015; 16(18):2045-54. DOI: 10.2217/pgs.15.138. View

Sohn M, Kim M, Han N, Kim I, Gim J, Min S . Whole exome sequencing for the identification of CYP3A7 variants associated with tacrolimus concentrations in kidney transplant patients. Sci Rep. 2018; 8(1):18064. PMC: 6305386. DOI: 10.1038/s41598-018-36085-w. View

Sawitzki B, Harden P, Reinke P, Moreau A, Hutchinson J, Game D . Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet. 2020; 395(10237):1627-1639. PMC: 7613154. DOI: 10.1016/S0140-6736(20)30167-7. View

Lee J, Huang H, Chen Y, Lu X . ABCB1 haplotype influences the sirolimus dose requirements in Chinese renal transplant recipients. Biopharm Drug Dispos. 2013; 35(3):164-72. DOI: 10.1002/bdd.1881. View

Sedrani R, Cottens S, Kallen J, SCHULER W . Chemical modification of rapamycin: the discovery of SDZ RAD. Transplant Proc. 1998; 30(5):2192-4. DOI: 10.1016/s0041-1345(98)00587-9. View

Sousa P, Estevinho M, Dias C, Ministro P, Kopylov U, Danese S . Thiopurines' Metabolites and Drug Toxicity: A Meta-Analysis. J Clin Med. 2020; 9(7). PMC: 7408995. DOI: 10.3390/jcm9072216. View

Lee J, Wang R, Yang Y, Lu X, Zhang X, Wang L . The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta-Analysis. Basic Clin Pharmacol Toxicol. 2014; 117(2):117-25. DOI: 10.1111/bcpt.12371. View

Chen Z, Zhang L, Yang C, Jiang Z, Shen H, Gui G . Effect of MDR1 C1236T polymorphism on cyclosporine pharmacokinetics: A systematic review and meta-analysis. Medicine (Baltimore). 2018; 96(47):e8700. PMC: 5708953. DOI: 10.1097/MD.0000000000008700. View

10.

Synold T, Dussault I, Forman B . The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med. 2001; 7(5):584-90. DOI: 10.1038/87912. View

11.

Cascorbi I . Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther. 2006; 112(2):457-73. DOI: 10.1016/j.pharmthera.2006.04.009. View

12.

Wysocki K, Seibert D . Pharmacogenomics in clinical care. J Am Assoc Nurse Pract. 2019; 31(8):443-446. DOI: 10.1097/JXX.0000000000000254. View

13.

Liu M, He H, Zhang Y, Hu Y, He F, Luo J . IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients. Acta Pharmacol Sin. 2017; 38(3):415-423. PMC: 5342670. DOI: 10.1038/aps.2016.153. View

14.

Moes D, Press R, den Hartigh J, der Straaten T, De Fijter J, Guchelaar H . Population pharmacokinetics and pharmacogenetics of everolimus in renal transplant patients. Clin Pharmacokinet. 2012; 51(7):467-80. DOI: 10.2165/11599710-000000000-00000. View

15.

Fredericks S, Jorga A, MacPhee I, Reboux S, Shiferaw E, Moreton M . Multi-drug resistance gene-1 (MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by C0 or C2 measurements. Clin Transplant. 2007; 21(2):252-7. DOI: 10.1111/j.1399-0012.2006.00635.x. View

16.

Hu Y, Qiu W, Liu Z, Zhu L, Liu Z, Tu J . Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. Clin Exp Pharmacol Physiol. 2006; 33(11):1093-8. DOI: 10.1111/j.1440-1681.2006.04492.x. View

17.

Sehgal S . Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998; 31(5):335-40. DOI: 10.1016/s0009-9120(98)00045-9. View

18.

Li D, Teng R, Zhu H, Fang Y . CYP3A4/5 polymorphisms affect the blood level of cyclosporine and tacrolimus in Chinese renal transplant recipients. Int J Clin Pharmacol Ther. 2013; 51(6):466-74. DOI: 10.5414/CP201836. View

19.

Ferraresso M, Belingheri M, Turolo S, Ghio L, Tirelli A, Grillo P . Long-term effects of ABCB1 and SXR SNPs on the systemic exposure to cyclosporine in pediatric kidney transplant patients. Pharmacogenomics. 2013; 14(13):1605-13. DOI: 10.2217/pgs.13.148. View

20.

Land W . The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. Transplantation. 2005; 79(5):505-14. DOI: 10.1097/01.tp.0000153160.82975.86. View