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Fan Q, Hui X, Li X, Li Q, Yang D, Wang Y. Reaching the cyclosporine a level target slowly in four weeks correlates with better prognosis for Chinese patients after allogeneic haematopoietic cell transplantation. Hematology 2023; 28:2275893. [PMID: 37975575 DOI: 10.1080/16078454.2023.2275893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 10/12/2023] [Indexed: 11/19/2023] Open
Abstract
OBJECTIVES This study investigated the impact of early cyclosporin A (CsA) initiation (day -5) on the risk of acute graft versus host disease (aGvHD) after allogeneic haematopoietic cell transplantation (allo-HSCT). METHODS Sixty-seven leukaemia patients who underwent allo-HSCT were investigated. The correlation between the CsA level in the first four weeks and the following indices was examined: GvHD, cumulative incidence (CI) of GvHD, CI of relapse at month 18, and non-relapse mortality (NRM) at month 18. RESULTS A significant association between aGvHD and CsA level in the fourth week after allo-HSCT was observed, with the incidence of aGvHD in the fourth week in the lower level group being higher than that in the higher level group (p = 0.044). The CI of aGvHD was 30.1% and 9.8% at day +90 and 42.3% and 17.1% at day +180 in the lower level and higher level groups, respectively. CONCLUSION For Chinese patients, early introduction and reaching the target CsA concentration within four weeks after allo-HSCT have a positive effect on preventing GvHD, especially in the fourth week after HSCT. Compared to the Western population, the target CsA concentration is lower and the time required to reach the target (within 4 weeks) is longer in the Chinese population (274.75 ng/mL).
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Affiliation(s)
- Qingqing Fan
- Department of Pharmacy, Jiangsu Province Hospital (The First Affiliated Hospital with Nanjing Medical University), Nanjing, People's Republic of China
| | - Xiang Hui
- Department of Pharmacy, Jiangsu Province Hospital (The First Affiliated Hospital with Nanjing Medical University), Nanjing, People's Republic of China
| | - Xiang Li
- Department of Pharmacy, Jiangsu Province Hospital (The First Affiliated Hospital with Nanjing Medical University), Nanjing, People's Republic of China
| | - Qian Li
- Department of Pharmacy, Jiangsu Province Hospital (The First Affiliated Hospital with Nanjing Medical University), Nanjing, People's Republic of China
| | - Dihong Yang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, People's Republic of China
| | - Yongqing Wang
- Department of Pharmacy, Jiangsu Province Hospital (The First Affiliated Hospital with Nanjing Medical University), Nanjing, People's Republic of China
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2
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Kim H, Han A, Ahn S, Min SK, Ha J, Min S. Association of high intra-patient variability in tacrolimus exposure with calcineurin inhibitor nephrotoxicity in kidney transplantation. Sci Rep 2023; 13:16502. [PMID: 37783764 PMCID: PMC10545770 DOI: 10.1038/s41598-023-43755-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 09/27/2023] [Indexed: 10/04/2023] Open
Abstract
Tacrolimus intra-patient variability (IPV) is a novel predictive marker for long-term kidney transplantation outcomes. We examined the association between IPV and calcineurin inhibitor (CNI) nephrotoxicity and the impact of pharmacogenes on CNI nephrotoxicity and IPV. Among kidney transplant recipients at our hospital between January 2013 and December 2015, the records of 80 patients who underwent 1-year protocol renal allograft biopsy and agreed to donate blood samples for genetic analysis were retrospectively reviewed. The cohort was divided into the low and high IPV groups based on a coefficient variability cutoff value (26.5%). In multivariate analysis, the IPV group was involved in determining CNI nephrotoxicity (HR 4.55; 95% CI 0.05-0.95; p = 0.043). The 5-year graft survival was superior in the low IPV group than in the high IPV group (100% vs 92.4% respectively, p = 0.044). Analysis of the time above therapeutic range (TATR) showed higher CNI nephrotoxicity in the high IPV with high TATR group than in the low IPV with low TATR group (35.7% versus 6.7%, p = 0.003). Genetic analysis discovered that CYP3A4 polymorphism (rs2837159) was associated with CNI nephrotoxicity (HR 28.23; 95% CI 2.2-355.9; p = 0.01). In conclusion, high IPV and CYP3A4 polymorphisms (rs2837159) are associated with CNI nephrotoxicity.
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Affiliation(s)
- Hyokee Kim
- Department of Surgery, Korea University College of Medicine, Seoul, South Korea
| | - Ahram Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Sanghyun Ahn
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung-Kee Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Jongwon Ha
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Sangil Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.
- Division of Transplantation and Vascular Surgery, Department of Surgery, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
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Turolo S, Edefonti A, Syren ML, Montini G. Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation. J Clin Med 2023; 12:4454. [PMID: 37445489 DOI: 10.3390/jcm12134454] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/16/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
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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Affiliation(s)
- Stefano Turolo
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, 20122 Milan, Italy
| | - Alberto Edefonti
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, 20122 Milan, Italy
| | - Marie Luise Syren
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Giovanni Montini
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
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The Effect of Voriconazole on Tacrolimus in Kidney Transplantation Recipients: A Real-World Study. Pharmaceutics 2022; 14:pharmaceutics14122739. [PMID: 36559231 PMCID: PMC9785881 DOI: 10.3390/pharmaceutics14122739] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection.
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Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients. Biomedicines 2022; 10:biomedicines10081798. [PMID: 35892699 PMCID: PMC9332547 DOI: 10.3390/biomedicines10081798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/18/2022] [Accepted: 07/22/2022] [Indexed: 12/17/2022] Open
Abstract
Immunosuppressant drugs (ISDs) are routinely used in clinical practice to maintain organ transplant survival. However, these drugs are characterized by a restricted therapeutic index, a high inter- and intra-individual pharmacokinetic variability, and a series of severe adverse effects. In particular, genetic factors have been estimated to play a role in this variability because of polymorphisms regarding genes encoding for enzymes and transporters involved in the ISDs pharmacokinetic. Several studies showed important correlations between genetic polymorphisms and ISDs blood levels in transplanted patients; therefore, this review aims to summarize the pharmacogenetics of approved ISDs. We used PubMed database to search papers on pharmacogenetics of ISDs in adults or pediatric patients of any gender and ethnicity receiving immunosuppressive therapy after kidney transplantation. We utilized as search term: “cyclosporine or tacrolimus or mycophenolic acid or sirolimus or everolimus and polymorphism and transplant”. Our data showed that polymorphisms in CYP3A5, CYP3A4, ABCB1, and UGT1A9 genes could modify the pharmacokinetics of immunosuppressants, suggesting that patient genotyping could be a helpful strategy to select the ideal ISDs dose for each patient.
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Significance of Ethnic Factors in Immunosuppressive Therapy Management After Organ Transplantation. Ther Drug Monit 2021; 42:369-380. [PMID: 32091469 DOI: 10.1097/ftd.0000000000000748] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Clinical outcomes after organ transplantation have greatly improved in the past 2 decades with the discovery and development of immunosuppressive drugs such as calcineurin inhibitors, antiproliferative agents, and mammalian target of rapamycin inhibitors. However, individualized dosage regimens have not yet been fully established for these drugs except for therapeutic drug monitoring-based dosage modification because of extensive interindividual variations in immunosuppressive drug pharmacokinetics. The variations in immunosuppressive drug pharmacokinetics are attributed to interindividual variations in the functional activity of cytochrome P450 enzymes, UDP-glucuronosyltransferases, and ATP-binding cassette subfamily B member 1 (known as P-glycoprotein or multidrug resistance 1) in the liver and small intestine. Some genetic variations have been found to be involved to at least some degree in pharmacokinetic variations in post-transplant immunosuppressive therapy. It is well known that the frequencies and effect size of minor alleles vary greatly between different races. Thus, ethnic considerations might provide useful information for optimizing individualized immunosuppressive therapy after organ transplantation. Here, we review ethnic factors affecting the pharmacokinetics of immunosuppressive drugs requiring therapeutic drug monitoring, including tacrolimus, cyclosporine, mycophenolate mofetil, sirolimus, and everolimus.
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Degraeve AL, Moudio S, Haufroid V, Chaib Eddour D, Mourad M, Bindels LB, Elens L. Predictors of tacrolimus pharmacokinetic variability: current evidences and future perspectives. Expert Opin Drug Metab Toxicol 2020; 16:769-782. [PMID: 32721175 DOI: 10.1080/17425255.2020.1803277] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION In kidney transplantation, tacrolimus (TAC) is at the cornerstone of current immunosuppressive strategies. Though because of its narrow therapeutic index, it is critical to ensure that TAC levels are maintained within this sharp window through reactive adjustments. This would allow maximizing efficiency while limiting drug-associated toxicity. However, TAC high intra- and inter-patient pharmacokinetic (PK) variability makes it more laborious to accurately predict the appropriate dosage required for a given patient. AREAS COVERED This review summarizes the state-of-the-art knowledge regarding drug interactions, demographic and pharmacogenetics factors as predictors of TAC PK. We provide a scoring index for each association to grade its relevance and we present practical recommendations, when possible for clinical practice. EXPERT OPINION The management of TAC concentration in transplanted kidney patients is as critical as it is challenging. Recommendations based on rigorous scientific evidences are lacking as knowledge of potential predictors remains limited outside of DDIs. Awareness of these limitations should pave the way for studies looking at demographic and pharmacogenetic factors as well as gut microbiota composition in order to promote tailored treatment plans. Therapeutic approaches considering patients' clinical singularities may help allowing to maintain appropriate concentration of TAC.
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Affiliation(s)
- Alexandra L Degraeve
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium.,Metabolism and Nutrition Research Group (Mnut), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium
| | - Serge Moudio
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium.,Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain , Brussels, Belgium
| | - Vincent Haufroid
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain , Brussels, Belgium.,Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc , Brussels, Belgium
| | - Djamila Chaib Eddour
- Kidney and Pancreas Transplantation Unit, Cliniques Universitaires Saint-Luc , Brussels, Belgium
| | - Michel Mourad
- Kidney and Pancreas Transplantation Unit, Cliniques Universitaires Saint-Luc , Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group (Mnut), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium
| | - Laure Elens
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique De Louvain , Brussels, Belgium.,Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain , Brussels, Belgium
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Worsening of Kidney Transplant Function During 2-Year Follow-up Is Associated With the Genetic Variants of CYP3A4, MDR1, and UGT1A9. Transplant Proc 2020; 52:2363-2367. [PMID: 32222391 DOI: 10.1016/j.transproceed.2020.02.088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/09/2020] [Accepted: 02/13/2020] [Indexed: 11/24/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNIs), tacrolimus and cyclosporine, undergo pharmacokinetic processes. Enzymes and transport proteins found in various organs are involved. It is possible that genetic polymorphisms of these proteins influence CNIs pharmacokinetics and the generation of CNIs metabolites. CNIs may be nephrotoxic, and it is thought that some CNIs' metabolites may have a similar effect. The study was aimed at the assessment of the relationship between selected gene polymorphisms for enzymes and transport proteins and change of estimated glomerular filtration rate (eGFR) during a 2-year follow-up in kidney transplant (KTX) patients. METHODS The study involved 366 patients after KTX (160 women; 43.7%) receiving tacrolimus (62.57%) and cyclosporine (37.43%). The mean age was 50.1 years, and the median time after KTX was 60.5 months. The study protocol conformed with the Declaration of Helsinki. The percent of difference between eGFR at baseline and at 24 months (ΔeGFR) was calculated. We evaluated selected genetic polymorphisms of CYP3A4, CYP3A5, MDR1, UGT1A9, UGT2B7, UGT1A8, and MRP2. RESULTS In the tacrolimus group, there were no significant differences of ΔeGFR between groups distinguished based on analyzed genotypes. In the cyclosporine group, differences were found for CYP3A4∗22 C/C -12.3 (-26.8 to -1.8) versus C/T 13.2 (12.4 to 13.9), P = .034; MDR1 3435C>T C/T -18.2 (-31.5 to -5.7) versus C/C -1.8 (-17.1 to 6.9) vs T/T -8.1 (-18.4 to 12.4), P = .031; and UGT1A9 2152C>T C/C -9.0 (-25.5 to 2.8) versus C/T -26.8 (-31.9 to -24.1), P = .017. CONCLUSION The study results suggest that in KTX metabolic transformations and transport, especially of cyclosporine, dependence on the genetic variability of CYP3A4, UGT1A9, and MDR1 may contribute to kidney damage.
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Wang Z, Zheng M, Yang H, Han Z, Tao J, Chen H, Sun L, Guo M, Wang L, Tan R, Wei JF, Gu M. Association of Genetic Variants in CYP3A4, CYP3A5, CYP2C8, and CYP2C19 with Tacrolimus Pharmacokinetics in Renal Transplant Recipients. Curr Drug Metab 2020; 20:609-618. [PMID: 31244435 DOI: 10.2174/1389200220666190627101927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/05/2019] [Accepted: 05/31/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Our study aimed to investigate the pharmacogenetics of cytochrome P3A4 (CYP3A4), CYP3A5, CYP2C8, and CYP2C19 and their influence on TAC Pharmacokinetics (PKs) in short-term renal transplant recipients. METHODS A total of 105 renal transplant recipients were enrolled. Target Sequencing (TS) based on next-generation sequencing technology was used to detect all exons, exon/intron boundaries, and flanking regions of CYP3A4, CYP3A5, CYP2C8, and CYP2C19. After adjustment of Minor Allele Frequencies (MAF) and Hardy-Weinberg Equilibrium (HWE) analysis, tagger Single-nucleotide Polymorphisms (SNPs) and haplotypes were identified. Influence of tagger SNPs on TAC concentrations was analyzed. RESULTS A total of 94 SNPs were identified in TS analysis. Nine tagger SNPs were selected, and two SNPs (rs15524 and rs4646453) were noted to be significantly associated with TAC PKs in short-term post-transplant follow-up. Measurement time points of TAC, body mass index (BMI), usage of sirolimus, and incidence of Delayed Graft Function (DGF) were observed to be significantly associated with TAC PKs. Three haplotypes were identified, and rs15524-rs4646453 was found to remarkably contribute to TAC PKs. Recipients carrying H2/H2 (GG-AA) haplotype also showed significantly high weight- and dose-adjusted TAC concentrations in posttransplant periods of 7, 14, and 30 days and 3 and 6 months. CONCLUSIONS Two tagger SNPs, namely, rs15524 and rs4646453, are significantly related to the variability of TAC disposition, and TAC measurement time points, BMI, usage of sirolimus, and incidence of DGF contribute to this influence. Recipients carrying H2/H2 (GG-AA) haplotype in rs15524-rs4646453 may require a low dosage of TAC during 1-year follow-up posttransplant.
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Affiliation(s)
- Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ming Zheng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Miao Guo
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Libin Wang
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ji-Fu Wei
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Abstract
This review is focused on present and future biomarkers, along with pharmacogenomics used in clinical practice for kidney transplantation. It aims to highlight biomarkers that could potentially be used to improve kidney transplant early and long-term graft survival, but also potentially patient co-morbidity. Future directions for improving outcomes are discussed, which include immune tolerance and personalising immunosuppression regimens.
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Oetting WS, Wu B, Schladt DP, Guan W, Remmel RP, Dorr C, Mannon RB, Matas AJ, Israni AK, Jacobson PA. Attempted validation of 44 reported SNPs associated with tacrolimus troughs in a cohort of kidney allograft recipients. Pharmacogenomics 2018; 19:175-184. [PMID: 29318894 PMCID: PMC6021962 DOI: 10.2217/pgs-2017-0187] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 12/15/2017] [Indexed: 02/07/2023] Open
Abstract
AIM Multiple genetic variants have been associated with variation in tacrolimus (TAC) trough concentrations. Unfortunately, additional studies do not confirm these associations, leading one to question if a reported association is accurate and reliable. We attempted to validate 44 published variants associated with TAC trough concentrations. MATERIALS & METHODS Genotypes of the variants in our cohort of 1923 kidney allograft recipients were associated with TAC trough concentrations. RESULTS Only variants in CYP3A4 and CYP3A5 were significantly associated with variation in TAC trough concentrations in our validation. CONCLUSION There is no evidence that common variants outside the CYP3A4 and CYP3A5 loci are associated with variation in TAC trough concentrations. In the future rare variants may be important and identified using DNA sequencing.
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Affiliation(s)
- William S Oetting
- Department of Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Baolin Wu
- Department of Biostatistics, University of Minnesota, Minneapolis, MN 55455, USA
| | - David P Schladt
- Minneapolis Medical Research Foundation, Minneapolis, MN 55404, USA
| | - Weihua Guan
- Department of Biostatistics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Rory P Remmel
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
| | - Casey Dorr
- Minneapolis Medical Research Foundation, Minneapolis, MN 55404, USA
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Roslyn B Mannon
- Division of Nephrology, University of Alabama, Birmingham, AL 35233, USA
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ajay K Israni
- Minneapolis Medical Research Foundation, Minneapolis, MN 55404, USA
- Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55415, USA
- Department of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 55455, USA
| | - Pamala A Jacobson
- Department of Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
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12
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Sun B, Guo Y, Gao J, Shi W, Fan G, Li X, Qiu J, Qin Y, Liu G. Influence of CYP3A and ABCB1 polymorphisms on cyclosporine concentrations in renal transplant recipients. Pharmacogenomics 2017; 18:1503-1513. [PMID: 28952408 DOI: 10.2217/pgs-2017-0127] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aim: Cyclosporine is a substrate of CYP3A and ABCB1. This study examined the role of CYP3A and ABCB1 polymorphisms on cyclosporine pharmacokinetics in renal transplant recipients. Patients & methods: CYP3A and ABCB1 SNPs were detected in 521 recipients. The relationships of dose-adjusted concentrations with corresponding genotypes were investigated at the different terms. Results: CYP3A5 rs776746 and CYP3A7 rs10211 genotype affect C0/D at the short-term, medium-term and long-term after transplantation (p < 0.05). CYP3A7 rs2257401 genotype affects C2/D at the medium-term (p < 0.05). CYP3A4 rs4646437, CYP3A5 rs776746 and CYP3A7 rs2257401 genotype affect C2/D at the long-term (p < 0.05). There are no relationships between ABCB1 polymorphism and cyclosporine C/D. Conclusion: CYP3A genetic factors (rs776746, rs4646437, rs2257401 and rs10211) were varied in different stages after transplantation. The role of CYP3A7 in cyclosporine metabolism requires further study.
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Affiliation(s)
- Bo Sun
- Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Yankun Guo
- Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Junwei Gao
- Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Weifeng Shi
- Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Guorong Fan
- Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Xiaoyu Li
- Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Jianxin Qiu
- Department of Renal Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Yan Qin
- Department of Renal Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Gaolin Liu
- Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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Liu S, Shi X, Tian X, Zhang X, Sun Z, Miao L. Effect of CYP3A4∗1G and CYP3A5∗3 Polymorphisms on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects. Front Pharmacol 2017; 8:176. [PMID: 28408884 PMCID: PMC5374142 DOI: 10.3389/fphar.2017.00176] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 03/16/2017] [Indexed: 01/01/2023] Open
Abstract
Ticagrelor is the first reversible, direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y12 receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. CYP3A polymorphisms have been well documented, and CYP3A4∗1G (g.20230G>A, rs2242480) and CYP3A5∗3 (g.6986A>G, rs776746) are the most important single nucleotide polymorphisms in Chinese. Genetic differences in CYP3A4 and CYP3A5 expression in human volunteers and patients might affect the clearance of ticagrelor or AR-C124910XX in vivo resulting in subsequent variable patient response. Thus, this study is designed to explore the effects of CYP3A4∗1G and CYP3A5∗3 polymorphisms on the pharmacokinetics and pharmcodynamics of ticagrelor in healthy Chinese subjects. The results indicated that the CYP3A4∗1G polymorphism significantly influenced the pharmacokinetics of AR-C124910XX, and it may be more important than CYP3A5∗3 with respect to influencing ticagrelor pharmacokinetics by increasing CYP3A4 activity. However, the significant effect of CYP3A4∗1G polymorphism on AR-C124910XX plasma levels did not translate into detectable effect on inhibition of platelet aggregation. Therefore, it seems not necessary to adjust the dosage of ticagrelor according to the CYP3A4 or 3A5 genotype.
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Affiliation(s)
- Shuaibing Liu
- Department of Pharmacy, The first affiliated Hospital of Zhengzhou UniversityZhengzhou, China
| | - Xiangfen Shi
- Department of Pharmacy, The first affiliated Hospital of Zhengzhou UniversityZhengzhou, China
| | - Xin Tian
- Department of Pharmacy, The first affiliated Hospital of Zhengzhou UniversityZhengzhou, China
| | - Xiaojian Zhang
- Department of Pharmacy, The first affiliated Hospital of Zhengzhou UniversityZhengzhou, China
| | - Zhiyong Sun
- Department of Pharmacy, The first affiliated Hospital of Zhengzhou UniversityZhengzhou, China
| | - Liyan Miao
- Department of Clinical Pharmacology Research Lab, The first affiliated Hospital of Soochow UniversitySuzhou, China
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Liu R, Cao J, Zhang Q, Shi XM, Pan XD, Dong R. Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement. Medicine (Baltimore) 2017; 96:e5658. [PMID: 28079798 PMCID: PMC5266160 DOI: 10.1097/md.0000000000005658] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis. Multiple linear regression was performed by incorporating patients' clinical and genetic data to create a new algorithm for warfarin dosing. From the 96 SNPs analyzed, VKORC1 rs9923231, CYP1A2 rs2069514, CYP3A4 rs28371759, and APOE rs7412 were associated with higher average warfarin maintenance doses, whereas CYP2C9 rs1057910, EPHX1 rs2260863, and CYP4F2 rs2189784 were associated with lower warfarin doses (P < 0.05). Multiple linear regression analysis could estimate 44.4% of warfarin dose variability consisting of, in decreasing order, VKORC1 rs9923231 (14.2%), CYP2C9*3 (9.6%), body surface area (6.7%), CYP1A2 rs2069514 (3.7%), age (2.7%), CYP3A4 rs28371759 (2.5%), CYP4F2 rs2108622 (1.9%), APOE rs7412 (1.7%), and VKORC1 rs2884737 (1.4%). In the dosing algorithm we developed, we confirmed the strongest effects of VKORC1, CYP2C9 on warfarin dosing. In the limited sample set, we also found that novel genetic predictors (CYP1A2, CYP3A4, APOE, EPHX1, CYP4F2, and VKORC1 rs2884737) may be associated with warfarin dosing. Further validation is needed to assess our results in larger independent northern Chinese samples.
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Affiliation(s)
- Rui Liu
- Department of Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing
| | - Jian Cao
- Department of Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing
| | - Qian Zhang
- Department of Epidemiology, Beijing Institute of Heart, Lung and Blood Vessel Disease
| | - Xin-Miao Shi
- Department of Pediatrics, Peking University First Hospital, Beijing
| | - Xiao-Dong Pan
- Experimental Center, Beijing Institute of Heart, Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Ran Dong
- Department of Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing
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15
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Rancic N, Dragojevic-Simic V, Vavic N, Kovacevic A, Segrt Z, Djordjevic N. Economic Evaluation of Pharmacogenetic Tests in Patients Subjected to Renal Transplantation: A Review of Literature. Front Public Health 2016; 4:189. [PMID: 27630984 PMCID: PMC5005394 DOI: 10.3389/fpubh.2016.00189] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 08/23/2016] [Indexed: 12/15/2022] Open
Abstract
Renal transplantation is the treatment of choice for the patients with end-stage renal failure. Genetic factors, among others, can influence variability in response to immunosuppressive drugs. Nowadays, due to restrictive health resources, the question arises whether routine pharmacogenetic analyses should be done in the renal transplant recipients or not. The aim of this literature review was to present the up-to-date information considering the economic feasibility of pharmacogenetic testing in patients subjected to renal transplantation. The organization United Network for Organ Sharing in the US estimated that total costs per renal transplant concerning these analyses were $334,300 in 2014. Pharmacogenetic testing prior to treatment initiation could be helpful to predict and assess treatment response and the risks for adverse drug reactions. This kind of testing before treatment initiation seems to be one of the most promising applications of pharmacokinetics. Although pharmacogenetic tests were found to be a cost-effective or cost-saving strategy in many cases, some authors represent another opinion. However, if the real costs of renal transplantation are recognized, the application of these tests in the standard daily practice could be considered more realistic, which additionally emphasizes the importance of future studies assessing their cost effectiveness.
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Affiliation(s)
- Nemanja Rancic
- Centre for Clinical Pharmacology, Military Medical Academy Medical Faculty, University of Defence , Belgrade , Serbia
| | - Viktorija Dragojevic-Simic
- Centre for Clinical Pharmacology, Military Medical Academy Medical Faculty, University of Defence , Belgrade , Serbia
| | - Neven Vavic
- Solid Organ Transplantation Center, Military Medical Academy , Belgrade , Serbia
| | - Aleksandra Kovacevic
- Centre for Clinical Pharmacology, Military Medical Academy Medical Faculty, University of Defence , Belgrade , Serbia
| | - Zoran Segrt
- Management of the Military Medical Academy, Military Medical Academy Medical Faculty, University of Defence , Belgrade , Serbia
| | - Natasa Djordjevic
- Department of Pharmacology and Toxicology, The Faculty of Medical Sciences, University of Kragujevac , Kragujevac , Serbia
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Bifano M, Adamczyk R, Hwang C, Kandoussi H, Marion A, Bertz RJ. An open-label investigation into drug-drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects. Clin Drug Investig 2016; 35:281-9. [PMID: 25896946 PMCID: PMC4544506 DOI: 10.1007/s40261-015-0279-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background and Objective Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir—a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)—and cyclosporine or tacrolimus in healthy subjects. Methods Healthy fasted subjects (aged 18–49 years; body mass index 18–32 kg/m2) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4–11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8–19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC–MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC–MS/MS methods. Results Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration–time curve of daclatasvir but did not affect its maximum observed concentration. Conclusion On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.
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Affiliation(s)
- Marc Bifano
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Robert Adamczyk
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Carey Hwang
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
| | - Hamza Kandoussi
- />Bristol-Myers Squibb Research and Development, Lawrenceville, NJ USA
| | | | - Richard J. Bertz
- />Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ 08534 USA
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17
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Zhao CY, Jiao Z, Mao JJ, Qiu XY. External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients. Br J Clin Pharmacol 2016; 81:891-907. [PMID: 26574188 DOI: 10.1111/bcp.12830] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Revised: 11/04/2015] [Accepted: 11/11/2015] [Indexed: 11/29/2022] Open
Abstract
AIM Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors. METHODS Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%), (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated. RESULTS Sixteen published models were evaluated. In prediction-based diagnostics, the PE% within ±30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non-linear kinetics were used. CONCLUSIONS The published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non-linear pharmacokinetics in modelling might be a promising approach to improving model predictability.
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Affiliation(s)
- Chen-Yan Zhao
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040
| | - Zheng Jiao
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040
| | - Jun-Jun Mao
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040.,Department of Clinical Pharmacy, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai, 201203, China
| | - Xiao-Yan Qiu
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040
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Zununi Vahed S, Ardalan M, Samadi N, Omidi Y. Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients. BIOIMPACTS : BI 2015; 5:45-54. [PMID: 25901296 PMCID: PMC4401167 DOI: 10.15171/bi.2015.12] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Revised: 06/07/2014] [Accepted: 06/09/2014] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The advent of calcineurin inhibitors (CNIs), as the leading immunosuppressive agents, not only has revolutionized the transplant medicine but also made it a better therapeutic intervention that guarantees the graft outcome and improves the survival rate of patients. However, genetic polymorphism(s) in the CNIs metabolic substrates genes (CYP3A4, CYP3A5) and their transporter such as P-glycoprotein (P-gp) can influence the CNIs metabolism and elicit some possible systemic and intra-renal exposures to drugs and/or metabolites with differential risk of nephrotoxicity, jeopardizing the transplantation. METHODS In the current study, we review the recent literatures to evaluate the effects of genetic polymorphisms of the genes involved in development of chronic calcineurin nephrotoxicity and progression of chronic allograft dysfunction (CAD) providing an extensive overview on their clinical impacts. RESULTS Identifying the inherited genetic basis for the inter-individual differences in terms of drug responses and determining the risk of calcineurin-mediated nephrotoxicity and CAD allow optimized personalized administration of these agents whith minimal adverse effects. CONCLUSION Pharmacogenetics characteristics of CYP isoforms (CYP3A) and efflux transporters (P-gp and MRP), involved in metabolism and extracellular transportation of the immunosuppressive CNIs, can be of pivotal information in the pharmacotherapy of the renal-transplant recipients. Such information can be used for the successes clinical interventions to attain an improved drug administration strategy with reduced rates of rejection and toxicity.
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Affiliation(s)
- Sepideh Zununi Vahed
- Research Center for Pharmaceutical Nanotechnology, School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Chronic Kidney Disease Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadreza Ardalan
- Research Center for Pharmaceutical Nanotechnology, School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Chronic Kidney Disease Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Research Center for Pharmaceutical Nanotechnology, School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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Li CJ, Li L. Tacrolimus in preventing transplant rejection in Chinese patients--optimizing use. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:473-85. [PMID: 25609922 PMCID: PMC4298305 DOI: 10.2147/dddt.s41349] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tacrolimus is a product of fermentation of Streptomyces, and belongs to the family of calcineurin inhibitors. It is a widely used immunosuppressive drug for preventing solid-organ transplant rejection. Compared to cyclosporine, tacrolimus has greater immunosuppressive potency and a lower incidence of side effects. It has been accepted as first-line treatment after liver and kidney transplantation. Tacrolimus has specific features in Chinese transplant patients; its in vivo pharmacokinetics, treatment regimen, dose and administration, and adverse-effect profile are influenced by multiple factors, such as genetics and the spectrum of primary diseases in the Chinese population. We reviewed the clinical experience of tacrolimus use in Chinese liver- and kidney-transplant patients, including the pharmacology of tacrolimus, the immunosuppressive effects of tacrolimus versus cyclosporine, effects of different factors on tacrolimus metabolism on Chinese patients, personalized medicine, clinical safety profile, and patient satisfaction and adherence. This article provides guidance for the rational and efficient use of tacrolimus in Chinese organ-transplant patients.
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Affiliation(s)
- Chuan-Jiang Li
- Department of Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Liang Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China
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20
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Elens L, Bouamar R, Shuker N, Hesselink DA, van Gelder T, van Schaik RHN. Clinical implementation of pharmacogenetics in kidney transplantation: calcineurin inhibitors in the starting blocks. Br J Clin Pharmacol 2014; 77:715-28. [PMID: 24118098 DOI: 10.1111/bcp.12253] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 09/03/2013] [Indexed: 01/08/2023] Open
Abstract
Pharmacogenetics has generated many expectations for its potential to individualize therapy proactively and improve medical care. However, despite the huge amount of reported genetic associations with either pharmacokinetics or pharmacodynamics of drugs, the translation into patient care is still slow. In fact, strong evidence for a substantial clinical benefit of pharmacogenetic testing is still limited, with a few exceptions. In kidney transplantation, established pharmacogenetic discoveries are being investigated for application in the clinic to improve efficacy and to limit toxicity associated with the use of immunosuppressive drugs, especially the frequently used calcineurin inhibitors (CNIs) tacrolimus and ciclosporin. The purpose of the present review is to picture the current status of CNI pharmacogenetics and to discuss the most promising leads that have been followed so far.
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Affiliation(s)
- Laure Elens
- Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), Brussels, Belgium; Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam
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22
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Hronová K, Šíma M, Světlík S, Matoušková O, Slanař O. Pharmacogenetics and immunosuppressive drugs. Expert Rev Clin Pharmacol 2014; 7:821-35. [PMID: 25301406 DOI: 10.1586/17512433.2014.966811] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Several candidate genes have been proposed as potential biomarkers for altered pharmacodynamics or pharmacokinetics of immunosuppressive drugs. However, there is usually only limited clinical evidence substantiating the implementation of biomarkers into clinical practice. Testing for thiopurine-S-methyltransferase polymorphisms has been put into routine clinical use quite widely, while the other pharmacogenetic tests are much less frequently used. Relatively good evidence appeared for tacrolimus-related biomarkers; thus, their utilization may be envisaged in the near future. Although the biomarkers related to mycophenolate, sirolimus or other drugs in the therapeutic class may be promising, further research is necessary to provide more robust evidence. The present review focuses on immunosuppressive drugs, excluding biological treatment.
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Affiliation(s)
- Karolína Hronová
- Department of Pharmacology, First Faculty of Medicine and General Teaching Hospital, Charles University in Prague, Albertov 4, CZ-128 00 Prague 2, Czech Republic
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23
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Provenzani A, Santeusanio A, Mathis E, Notarbartolo M, Labbozzetta M, Poma P, Provenzani A, Polidori C, Vizzini G, Polidori P, D’Alessandro N. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol 2013; 19:9156-9173. [PMID: 24409044 PMCID: PMC3882390 DOI: 10.3748/wjg.v19.i48.9156] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 10/16/2013] [Accepted: 10/22/2013] [Indexed: 02/06/2023] Open
Abstract
The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.
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Chiu KW, Nakano T, Chen KD, Hsu LW, Lai CY, Chiu HC, Huang CY, Cheng YF, Goto S, Chen CL. Homogeneous phenomenon of the graft when using different genotype characteristic of recipients/donors in living donor liver transplantation. World J Hepatol 2013; 5:642-648. [PMID: 24303093 PMCID: PMC3847948 DOI: 10.4254/wjh.v5.i11.642] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Revised: 09/28/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the evidence of homogeneous phenomenon on CYP3A5*3 MDR1-3435 and CYP3A4*18 of the liver graft after living donor liver transplantation (LDLT).
METHODS: We identified the proportional change of the CYP3A5*3, MDR1-3435 and CYP3A4*18 from the peripheral blood mononuclear cell of 41 pairs recipient/donor with different genotype polymorphisms and 119 liver graft biopsy samples used with the pyrosequencing technique after LDLT. Polymerase chain reaction/ligase detection reaction assay and restriction fragment length polymorphism was employed for genotyping the CYP3A5*3 and CYP3A4*18 single nucleotide polymorphisms (SNPs). All of the recipients and donors expressed with the similar SNP genotype of CYP3A5*3, MDR1-3435 or CYP3A4*18 were excluded.
RESULTS: The final genetic polymorphisms of the liver graft biopsy samples of CYP3A5*3, MDR1-3435 and CYP3A4*18 was predominated depends on the donor with restriction fragment length polymorphism and seems to be less related to the recipient. The proportional changes of G to A alleles of the 119 samples of CYP3A5*3 (included A > A/G, A/G > A, A/G > G, G > A, G > A/G and A > G), C to T alleles of the 108 samples of MDR1-3435 (included C > C/T, C/T > C, C/T > T, T > C/T and T > C), and T to C alleles of 15 samples of CYP3A4*18 (included T/C > T and T > C/T) were significant different between the recipients and the liver graft biopsy samples (P < 0.0001) and less difference when compared with the donors in the pyrosequencing analysis after LDLT.
CONCLUSION: The CYP3A5*3, MDR1-3435 and CYP3A4*18 of the recipient could be modified by the donor so-called homogenous phenomenon when the recipient’s blood drained into the liver graft.
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