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1
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Hussaini SA, Waziri B, Dickens C, Duarte R. Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review. Pharmacogenomics 2024; 25:329-341. [PMID: 39109483 PMCID: PMC11404701 DOI: 10.1080/14622416.2024.2370761] [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: 03/16/2024] [Accepted: 06/18/2024] [Indexed: 09/13/2024] Open
Abstract
Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.
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Affiliation(s)
- Sadiq Aliyu Hussaini
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Internal Medicine, Ibrahim Badamasi Babangida Specialist Hospital, Minna, Nigeria
- Department of Pharmacology, Ibrahim Badamasi Babangida University, Lapai, Nigeria
| | - Bala Waziri
- Department of Internal Medicine, Ibrahim Badamasi Babangida Specialist Hospital, Minna, Nigeria
| | - Caroline Dickens
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Raquel Duarte
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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2
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Kwakyi E, Nartey ET, Otabil MK, Asiedu-Gyekye I, Ahorhorlu SY, Bioma V, Kudzi W. A descriptive study of the single-nucleotide polymorphisms known to affect the Tacrolimus trough concentration per dose, among a population of kidney failure patients in a tertiary hospital in Ghana. BMC Res Notes 2024; 17:210. [PMID: 39080672 PMCID: PMC11288130 DOI: 10.1186/s13104-024-06868-8] [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: 11/11/2023] [Accepted: 07/16/2024] [Indexed: 08/03/2024] Open
Abstract
BACKGROUND The burden of chronic kidney disease (CKD) and kidney failure in Ghana is on the ascendency, with the prevalence of CKD estimated at 13.3%. Patients with CKD who progress to kidney failure require life sustaining kidney replacement therapy (KRT) which is almost exclusively available in Ghana as haemodialysis. Kidney transplantation is considered the best KRT option for patients with irreversible kidney failure due to its relative cost efficiency as well as its superiority in terms of survival and quality of life. However, because transplants may trigger an immune response with potential organ rejection, immunosuppressants such as tacrolimus dosing are required. OBJECTIVE This study sought to determine single nucleotide polymorphisms in CYP3A5, CYP3A4 and MDR1 genes that affect the pharmacokinetics of Tacrolimus in a population of Ghanaian patients with kidney failure. METHOD This cross-sectional study comprised of 82 kidney failure patients undergoing maintenance haemodialysis at the Renal and Dialysis unit of Korle-Bu Teaching Hospital (KBTH). Clinical and demographic data were collected and genomic DNA isolated. Samples were genotyped for specific SNPs using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RESULTS Participants, 58/82 (70.73%) harbored the wildtype CYP3A5*1/*1 AA genotype, 20/82 (24.39%) carried the heterozygous CYP3A5*1/*3 AG genotype, and 4/82 (4.88%) had the homozygous mutant CYP3A5*3/*3 GG genotype. Also, 6/82 (7.32%) carried the wildtype AA genotype, 11/82 (13.41%) had the heterozygous AG genotype, and 65/82 (79.27%) harbored the homozygous mutant GG genotype of CYP3A4*1B (-290 A>G). For MDR1_Ex21 (2677 G>T), 81/82 (98.78%) carried the wildtype GG genotype, while 1/82 (1.22%) had the heterozygous GT genotype. For MDR1_Ex26 (3435 C>T), 63/82 (76.83%) had the wildtype CC genotype, while 18/82 (21.95%) carried the heterozygous CT genotype, and 1/82 (1.22%) harbored the mutant TT genotype. CONCLUSION SNPs in CYP3A4, CYP3A5, and MDR1 genes in a population of Ghanaian kidney failure patients were described. The varying SNPs of the featured genes suggest the need to consider the genetic status of Ghanaians kidney failure patients prior to transplantation and tacrolimus therapy.
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Affiliation(s)
- Edward Kwakyi
- Department of Medicine, University of Ghana Medical School, Legon, Ghana
| | - Edmund Tetteh Nartey
- Center for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of Ghana, P.O. Box GP 4236, Legon, Accra, Ghana.
| | - Michael Kobina Otabil
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Ghana, Legon, Ghana
| | - Isaac Asiedu-Gyekye
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Ghana, Legon, Ghana
| | - Samuel Yao Ahorhorlu
- Center for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of Ghana, P.O. Box GP 4236, Legon, Accra, Ghana
| | - Vincent Bioma
- Department of Medicine, University of Ghana Medical School, Legon, Ghana
| | - William Kudzi
- Center for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of Ghana, P.O. Box GP 4236, Legon, Accra, Ghana
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3
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Wanas H, Kamel MH, William EA, Fayad T, Abdelfattah ME, Elbadawy HM, Mikhael ES. The impact of CYP3A4 and CYP3A5 genetic variations on tacrolimus treatment of living-donor Egyptian kidney transplanted patients. J Clin Lab Anal 2023; 37:e24969. [PMID: 37789683 PMCID: PMC10681408 DOI: 10.1002/jcla.24969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 08/21/2023] [Accepted: 09/20/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Tacrolimus (TAC) is the mainstay of immunosuppressive regimen for kidney transplantations. Its clinical use is complex due to high inter-individual variations which can be partially attributed to genetic variations at the metabolizing enzymes CYP3A4 and CYP3A5. Two single nucleotide polymorphisms (SNPs), CYP3A4*22 and CYP3A5*3, have been reported as important causes of differences in pharmacokinetics that can affect efficacy and/or toxicity of TAC. OBJECTIVE Investigating the effect of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration in Egyptian renal recipients. METHODS Overall, 72 Egyptian kidney transplant recipients were genotyped for CYP3A4*22 G>A and CYP3A5*3 T>C. According to the functional defect associated with CYP3A variants, patients were clustered into: poor (PM) and non-poor metabolizers (Non-PM). The impact on dose adjusted through TAC concentrations (C0) and daily doses at different time points after transplantation was evaluated. RESULTS Cyp3A4*1/*22 and PM groups require significantly lower dose of TAC (mg/kg) at different time points with significantly higher concentration/dose (C0/D) ratio at day 10 in comparison to Cyp3A4*1/*1 and Non-PM groups respectively. However, CyP3A5*3 heterozygous individuals did not show any significant difference in comparison to CyP3A5*1/*3 individuals. By comparing between PM and Non-PM, the PM group had a significantly lower rate of recipients not reaching target C0 at day 14. CONCLUSION This is the first study on Egyptian population to investigate the impact of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration. This study and future multicenter studies can contribute to the individualization of TAC dosing in Egyptian patients.
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Affiliation(s)
- Hanaa Wanas
- Medical Pharmacology DepartmentFaculty of Medicine Cairo UniversityCairoEgypt
- Pharmacology and Toxicology Department, Faculty of PharmacyTaibah UniversityMadinahSaudi Arabia
| | - Mai Hamed Kamel
- Clinical and Chemical Pathology DepartmentFaculty of Medicine Cairo UniversityCairoEgypt
| | - Emad Adel William
- National Research Centre, Medical Research and Clinical Studies InstituteCairoEgypt
| | - Tarek Fayad
- Internal Medicine DepartmentFaculty of Medicine Cairo UniversityCairoEgypt
| | | | | | - Emily Samir Mikhael
- Clinical and Chemical Pathology DepartmentFaculty of Medicine Cairo UniversityCairoEgypt
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Reininger KA, Onyeaghala G, Anderson-Haag T, Schladt DS, Wu B, Guan W, Dorr CR, Remmel RP, Mannon R, Matas AJ, Oetting WS, Stahler P, Israni AK, Jacobson PA. Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers. Clin Transplant 2023; 37:e14893. [PMID: 36571802 PMCID: PMC10089949 DOI: 10.1111/ctr.14893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022]
Abstract
Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians). Time to first therapeutic concentration, percentage of time in therapeutic range (TTR), and estimated glomerular filtration rate (eGFR) were also evaluated. Fifty-five kidney transplant recipients were CYP3A5 poor metabolizers (PM), 17 were intermediate metabolizers (IM), and 6 were extensive metabolizers (EM). Compared to PMs, EMs/IMs had significantly more dose adjustments (6.1 vs. 8.1, p = .015). Overall, 33.82% of trough measurements resulted in a dose change. There was no difference in the number of tacrolimus trough measurements between PMs and EM/IMs. The total daily tacrolimus dose requirements were higher in EMs and IMs compared to PMs (<.001). TTR was ∼50% in the PMs and EMs/IMs groups. CYP3A5 EM/IM metabolizers have more tacrolimus dose changes and higher dose requirements which increases clinical management complexity. Larger studies are needed to assess the cost and benefits of including genotyping data to improve clinical management.
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Affiliation(s)
- Kevin A Reininger
- Department of Pharmacy, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - Guillaume Onyeaghala
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, USA
- Division of Nephrology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota, USA
| | - Teresa Anderson-Haag
- Department of Pharmacy, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - David S Schladt
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, USA
| | - Baolin Wu
- Department of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Weihua Guan
- Department of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Casey R Dorr
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, USA
- Division of Nephrology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota, USA
| | - Rory P Remmel
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA
| | - Roslyn Mannon
- Division of Nephrology, University of Nebraska, Omaha, Nebraska, USA
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - William S Oetting
- Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Paul Stahler
- Division of Surgery, Hennepin Healthcare, Minneapolis, Minnesota, USA
| | - Ajay K Israni
- Division of Nephrology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
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Warzyszyńska K, Zawistowski M, Karpeta E, Jałbrzykowska A, Kosieradzki M. CYP3A5 Expressor Genotype of the Transplanted Kidney Increases the Risk of Preterm Graft Loss and Acute Rejection. Nephron Clin Pract 2023; 147:441-450. [PMID: 36630936 DOI: 10.1159/000528109] [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: 04/06/2022] [Accepted: 10/25/2022] [Indexed: 01/12/2023] Open
Abstract
INTRODUCTION Tacrolimus is metabolized mainly in the liver by the CYP3A enzyme family, with a particularly well-documented role of CYP3A5. CYP3A5 is also expressed in the renal tissue and is present in the transplanted kidney. To date, the association between donor CYP3A5 polymorphisms and transplant outcome remains poorly understood. The aim of this study was to assess the effect of donor CYP3A5 expression on early and long-term transplant outcomes. METHODS A retrospective cohort study including 207 patients who received kidney grafts from 110 deceased donors was conducted at a single Central European Center. Tissue samples from all donors were studied for CYP3A5 single-nucleotide polymorphism (rs776746). Death-censored graft loss within 5-year follow-up, acute rejection occurrence, and kidney function, measured using serum creatinine and MDRD eGFR, were compared between groups of patients with allografts from rs776746 carriers (CYP3A5 expressors) and noncarriers (CYP3A5 nonexpressors). RESULTS Recipients who received kidneys from CYP3A5 expressors (n = 24) were at significantly higher risk of death-censored graft loss within 5-year follow-up (adjusted HR, 95% CI: 6.82, 2.01-23.12; p = 0.002) and acute rejection within the 1st posttransplant year (adjusted OR, 95% CI: 4.62, 1.67-12.77; p = 0.003) than those who did not (n = 183). The median time to loss of function was 1.93 [IQR; 0.77-3.19] years. CONCLUSIONS Donor CYP3A5 expressor status is associated with worse renal graft survival and a higher risk of acute rejection. Determination of donor CYP3A5 genotype is a potentially useful tool that may improve kidney transplant outcomes.
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Affiliation(s)
- Karola Warzyszyńska
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Michał Zawistowski
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
- Military Institute of Medicine, Warsaw, Poland
| | - Edyta Karpeta
- Department of Surgical and Transplantation Nursing and Extracorporeal Therapies, Medical University of Warsaw, Warsaw, Poland
| | | | - Maciej Kosieradzki
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
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Islam F, Islam MR, Nafady MH, Faysal M, Khan SL, Zehravi M, Emran TB, Rahman MH. Pharmacogenomics of immunosuppressants. Pharmacogenomics 2023:323-344. [DOI: 10.1016/b978-0-443-15336-5.00003-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023] Open
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Rodriguez-Antona C, Savieo JL, Lauschke VM, Sangkuhl K, Drögemöller BI, Wang D, van Schaik RHN, Gilep AA, Peter AP, Boone EC, Ramey BE, Klein TE, Whirl-Carrillo M, Pratt VM, Gaedigk A. PharmVar GeneFocus: CYP3A5. Clin Pharmacol Ther 2022; 112:1159-1171. [PMID: 35202484 PMCID: PMC9399309 DOI: 10.1002/cpt.2563] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/11/2022] [Indexed: 01/31/2023]
Abstract
The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP3A5 gene. Genetic variation within the CYP3A5 gene locus impacts the metabolism of several clinically important drugs, including the immunosuppressants tacrolimus, sirolimus, cyclosporine, and the benzodiazepine midazolam. Variable CYP3A5 activity is of clinical importance regarding tacrolimus metabolism. This GeneFocus provides a CYP3A5 gene summary with a focus on aspects regarding standardized nomenclature. In addition, this review also summarizes recent changes and updates, including the retirement of several allelic variants and provides an overview of how PharmVar CYP3A5 star allele nomenclature is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).
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Affiliation(s)
- Cristina Rodriguez-Antona
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | | | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Katrin Sangkuhl
- Department of Biomedical Data Science, Stanford University, Stanford, California, USA
| | - Britt I Drögemöller
- Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- CancerCare Manitoba Research Institute, Winnipeg, Manitoba, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada
| | - Danxin Wang
- Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Andrei A Gilep
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
- Institute of Biomedical Chemistry, Moscow, Russia
| | - Arul P Peter
- Coriell Life Sciences, Philadelphia, Pennsylvania, USA
| | - Erin C Boone
- Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | | | - Teri E Klein
- Department of Biomedical Data Science, Stanford University, Stanford, California, USA
| | | | - Victoria M Pratt
- Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Andrea Gaedigk
- Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA
- School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
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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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Andrews LM, de Winter BCM, Cornelissen EAM, de Jong H, Hesselink DA, Schreuder MF, Brüggemann RJM, van Gelder T, Cransberg K. A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement. Clin Pharmacokinet 2021; 59:591-603. [PMID: 31654367 PMCID: PMC7217818 DOI: 10.1007/s40262-019-00831-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background and Objective Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. Methods This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). Results At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. Conclusions The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers. Electronic supplementary material The online version of this article (10.1007/s40262-019-00831-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Louise M Andrews
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
| | - Brenda C M de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Elisabeth A M Cornelissen
- Department of Pediatric Nephrology, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Huib de Jong
- Department of Pediatric Nephrology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Michiel F Schreuder
- Department of Pediatric Nephrology, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands
| | | | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Karlien Cransberg
- Department of Pediatric Nephrology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
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10
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Xu Q, Yu F, Hao Z, Wu W, Sun Y, Wang T, Li G, Lv Q, Hu Z. Metabolism and transporter based drug–drug interaction of tacrolimus with nine co-medicated injections. MEDICINE IN DRUG DISCOVERY 2021. [DOI: 10.1016/j.medidd.2021.100091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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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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12
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Cheung CY, Chan KM, Wong YT, Chak WL, Bekers O, van Hooff JP. Influence of CYP3A5 Genetic Polymorphism on Long-Term Renal Function in Chinese Kidney Transplant Recipients Using Limited Sampling Strategy and Abbreviated Area Under the Curve for Tacrolimus Monitoring. Prog Transplant 2020; 30:249-253. [PMID: 32552577 DOI: 10.1177/1526924820933823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Although the association between CYP3A5 gene polymorphism and tacrolimus dosing requirements was well established, the impact on how CYP3A5 genotype affects the acute rejection and long-term renal function in patients who received kidney transplants and were treated with tacrolimus remained controversial. DESIGN Sixty-seven Chinese patients with kidney transplants receiving de novo tacrolimus-based immunosuppressive therapy with known CYP3A5 genotype were divided into 2 groups. Those with at least 1 CYP3A5*1 allele were CYP3A5 expressers while homozygotes for the mutant allele CYP3A5*3 were nonexpressers. Instead of trough level, our center used abbreviated area under the curve for tacrolimus monitoring. Primary outcome was the long-term renal function between both groups while secondary outcomes included the weight-adjusted daily tacrolimus dose, graft survival, incidence of biopsy-proven acute rejection (BPAR), opportunistic infection, and cancer. RESULTS Thirty-five (52.2%) patients were CYP3A5 expressers while 32 were nonexpressers. Mean daily tacrolimus dose in the CYP3A5 expressers and nonexpressers was 0.08 (0.03) and 0.05 (0.02) mg/kg, respectively (P < .01). Starting from 1-month posttransplant, the renal function was comparable between both groups, which persisted up to 10-year. Ten patients experienced BPAR rejection and there was no significant difference in the rejection-free survival between both groups (P = .87). There was also no significant difference in the death-censored graft survival between both groups (P = .86). Finally, the incidence of opportunistic infection and posttransplant cancer was similar between them. DISCUSSION There was no significant difference in renal function, graft survival, and acute rejection between CYP3A5 expressers and nonexpressers.
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Affiliation(s)
- Chi Yuen Cheung
- Renal Unit, Department of Medicine, 156451Queen Elizabeth Hospital, Hong Kong
| | - Koon Ming Chan
- Renal Unit, Department of Medicine, 156451Queen Elizabeth Hospital, Hong Kong
| | - Yuen Ting Wong
- Renal Unit, Department of Medicine, 156451Queen Elizabeth Hospital, Hong Kong
| | - Wai Leung Chak
- Renal Unit, Department of Medicine, 156451Queen Elizabeth Hospital, Hong Kong
| | - Otto Bekers
- Department of Clinical Chemistry, Central Diagnostic Laboratory, 199236Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Johannes P van Hooff
- Department of Internal Medicine, 199236Maastricht University Medical Centre, Maastricht, the Netherlands
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13
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Pallio G, Irrera N, Bitto A, Mannino F, Minutoli L, Rottura M, Pallio S, Altavilla D, Alibrandi A, Marciano MC, Righi M, Mannucci C, Arcoraci V, Squadrito F. Failure of Achieving Tacrolimus Target Blood Concentration Might Be Avoided by a Wide Genotyping of Transplanted Patients: Evidence from a Retrospective Study. J Pers Med 2020; 10:jpm10020047. [PMID: 32492825 PMCID: PMC7354451 DOI: 10.3390/jpm10020047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/22/2020] [Accepted: 05/29/2020] [Indexed: 01/08/2023] Open
Abstract
Precise tacrolimus treatment in transplanted patients is achieved in the clinical setting by performing therapeutic drug monitoring (TDM) and consequently adjusting therapy. The aim of this study was to retrospectively analyze the variability in tacrolimus blood levels throughout 2 years of observation in 75 transplanted patients and to investigate if tacrolimus blood levels correlate with presence of genetic polymorphisms, thus modifying tacrolimus pharmacokinetics. CYP3A5*1 (G6986A), CYP3A4*1B (A392G), CYP3A4*22, ABCB1 (C3435T; C1236T; G2677A/T), SLCO1B1 (T521C), polymorphisms were analyzed. Based on the effect of their genotypes, patients were stratified into 5 groups: (1) reduced tacrolimus metabolism (RM), (2) increased metabolism (IM), (3) transporters polymorphisms (TM), (4) metabolism and transporter polymorphisms (AM) and (5) no mutations (Wild Type, WT). The percentage of the samples out of therapeutic range was significantly higher in the IM group than in the WT group (p = 0.001), as well as compared to the TM group (p = 0.004). Only IM pattern (p = 0.015) resulted as an independent predictor of number of tacrolimus blood levels out of therapeutic range. RM pattern (p = 0.006) was inversely related to the administered dose. Therefore, genotyping could become a standard practice before tacrolimus prescription thus decreasing side effects, increasing efficacy and reducing the economic burden for the national health system.
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Affiliation(s)
- Giovanni Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Natasha Irrera
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Federica Mannino
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Michelangelo Rottura
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Socrate Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Domenica Altavilla
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy; (D.A.); (M.R.); (C.M.)
| | - Angela Alibrandi
- Department of Economics Section of Statistical and Mathematical Sciences, University of Messina, Via dei Verdi, 98122 Messina, Italy;
| | - Maria Concetta Marciano
- Grande Ospedale Metropolitano: “Bianchi-Melacrino-Morelli”, Via Giuseppe Melacrino, 89124 Reggio Calabria, Italy;
| | - Maria Righi
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy; (D.A.); (M.R.); (C.M.)
| | - Carmen Mannucci
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy; (D.A.); (M.R.); (C.M.)
| | - Vincenzo Arcoraci
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
- Correspondence:
| | - Francesco Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
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14
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Yanik MV, Seifert ME, Locke JE, Hauptfeld-Dolejsek V, Crowley MR, Cutter GR, Mannon RB, Feig DI, Limdi NA. CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients. Pediatr Transplant 2019; 23:e13494. [PMID: 31124575 PMCID: PMC8009482 DOI: 10.1111/petr.13494] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 03/30/2019] [Accepted: 04/23/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear. METHODS We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non-expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post-transplant. RESULTS The study cohort included 55 (56%) expressers and 43 (44%) non-expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non-expressers (log rank, P = 0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P = 0.16). Early biopsy-proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non-expressers. CONCLUSIONS Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non-expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes.
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Affiliation(s)
- Megan V. Yanik
- Division of Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Michael E. Seifert
- Division of Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jayme E. Locke
- Department of Surgery, Division of Transplantation, University of Alabama at Birmingham, Birmingham, Alabama
| | - Vera Hauptfeld-Dolejsek
- Department of Surgery, Division of Transplantation, University of Alabama at Birmingham, Birmingham, Alabama
| | - Michael R. Crowley
- Heflin Center for Genomic Science, University of Alabama at Birmingham, Birmingham, Alabama
| | - Gary R. Cutter
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Roslyn B. Mannon
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Daniel I. Feig
- Division of Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Nita A. Limdi
- Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama
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15
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Andrews LM, Hesselink DA, van Gelder T, Koch BCP, Cornelissen EAM, Brüggemann RJM, van Schaik RHN, de Wildt SN, Cransberg K, de Winter BCM. A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation. Clin Pharmacokinet 2019; 57:475-489. [PMID: 28681225 PMCID: PMC5856873 DOI: 10.1007/s40262-017-0567-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Background Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration. Objectives The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis. Methods A total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM®) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines. Results The data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day. Conclusion During the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor.
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Affiliation(s)
- Louise M Andrews
- Department of Hospital Pharmacy, Erasmus Medical Center, University Medical Center Rotterdam, P. O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus Medical Center, University Medical Center Rotterdam, P. O. Box 2040, 3000 CA, Rotterdam, The Netherlands.,Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Birgit C P Koch
- Department of Hospital Pharmacy, Erasmus Medical Center, University Medical Center Rotterdam, P. O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Elisabeth A M Cornelissen
- Department of Pediatric Nephrology, Radboud University Medical Centre, Amalia Children's Hospital, Nijmegen, The Netherlands
| | | | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Saskia N de Wildt
- Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands
| | - Karlien Cransberg
- Department of Pediatric Nephrology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Brenda C M de Winter
- Department of Hospital Pharmacy, Erasmus Medical Center, University Medical Center Rotterdam, P. O. Box 2040, 3000 CA, Rotterdam, The Netherlands
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16
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Andrews LM, Hesselink DA, van Schaik RHN, van Gelder T, de Fijter JW, Lloberas N, Elens L, Moes DJAR, de Winter BCM. A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients. Br J Clin Pharmacol 2019; 85:601-615. [PMID: 30552703 PMCID: PMC6379219 DOI: 10.1111/bcp.13838] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 11/30/2018] [Accepted: 12/10/2018] [Indexed: 12/16/2022] Open
Abstract
Aims The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient. Methods Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed‐effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. Results A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two‐compartment model. The mean absorption rate was 3.6 h−1, clearance was 23.0 l h–1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose:
Dosemg=222nghml–1*22.5lh–1*1.0ifCYP3A5*3/*3or1.62ifCYP3A5*1/*3orCYP3A5*1/*1*1.0ifCYP3A4*1or unknownor0.814ifCYP3A4*22*Age56−0.50*BSA1.930.72/1000Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model. Conclusions For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.
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Affiliation(s)
- L M Andrews
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - D A Hesselink
- Department of Internal Medicine, Division of Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Rotterdam Transplant Group, Rotterdam, The Netherlands
| | - R H N van Schaik
- Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - T van Gelder
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Internal Medicine, Division of Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Rotterdam Transplant Group, Rotterdam, The Netherlands
| | - J W de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - N Lloberas
- Department of Nephrology, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - L Elens
- Department of Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), Brussels, Belgium
| | - D J A R Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - B C M de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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17
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Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation. Pharmacogenet Genomics 2019; 29:9-17. [DOI: 10.1097/fpc.0000000000000360] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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18
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Yu M, Liu M, Zhang W, Ming Y. Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation. Curr Drug Metab 2018; 19:513-522. [PMID: 29380698 PMCID: PMC6182932 DOI: 10.2174/1389200219666180129151948] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 10/03/2017] [Accepted: 10/13/2017] [Indexed: 01/10/2023]
Abstract
Background: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immu-nosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynam-ics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug. Method: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms. Results: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac. Conclusion: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse ef-fects or drug inefficacy
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Affiliation(s)
- Meng Yu
- Transplantation center, The 3rd Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Mouze Liu
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, China
| | - Wei Zhang
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, China
| | - Yingzi Ming
- Transplantation center, The 3rd Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
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19
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Hu R, Barratt DT, Coller JK, Sallustio BC, Somogyi AA. CYP3A5*3
and ABCB1
61A>G Significantly Influence Dose-adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post-Kidney Transplantation. Basic Clin Pharmacol Toxicol 2018; 123:320-326. [DOI: 10.1111/bcpt.13016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 03/20/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Rong Hu
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
| | - Daniel T. Barratt
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
| | - Janet K. Coller
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
| | - Benedetta C. Sallustio
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
- Department of Pharmacology; Queen Elizabeth Hospital; Adelaide SA Australia
| | - Andrew A. Somogyi
- Discipline of Pharmacology; Adelaide Medical School; University of Adelaide; Adelaide SA Australia
- Department of Clinical Pharmacology; Royal Adelaide Hospital; Adelaide SA Australia
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20
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Yang J, Claas FHJ, Eikmans M. Genome-wide association studies in kidney transplantation: Advantages and constraints. Transpl Immunol 2018; 49:1-4. [PMID: 29704558 DOI: 10.1016/j.trim.2018.04.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 04/23/2018] [Indexed: 01/03/2023]
Abstract
Since the discovery of the human leukocyte antigen (HLA) system, the role of HLA molecules in the field of transplantation has been appreciated: better matching leads to better graft function. Since then, the association of other genetic polymorphisms with clinical outcome has been investigated in many studies. Genome-wide association studies (GWAS) represent a powerful tool to identify causal genetic variants, by simultaneously analyzing millions of single nucleotide polymorphisms scattered across the genome. GWAS in transplantation may indeed be useful to reveal novel markers that may potentially be involved in the mechanism of allograft rejection and graft failure. However, the relevance of GWAS for risk stratification or donor selection for an individual patient is limited as is already reflected by the fact that many parameters, significant in one study, cannot be confirmed in another one.
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Affiliation(s)
- Jianxin Yang
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Frans H J Claas
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Eikmans
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
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21
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Thishya K, Vattam KK, Naushad SM, Raju SB, Kutala VK. Artificial neural network model for predicting the bioavailability of tacrolimus in patients with renal transplantation. PLoS One 2018; 13:e0191921. [PMID: 29621269 PMCID: PMC5886400 DOI: 10.1371/journal.pone.0191921] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/12/2018] [Indexed: 02/06/2023] Open
Abstract
The objective of the current study was to explore the role of ABCB1 and CYP3A5 genetic polymorphisms in predicting the bioavailability of tacrolimus and the risk for post-transplant diabetes. Artificial neural network (ANN) and logistic regression (LR) models were used to predict the bioavailability of tacrolimus and risk for post-transplant diabetes, respectively. The five-fold cross-validation of ANN model showed good correlation with the experimental data of bioavailability (r2 = 0.93-0.96). Younger age, male gender, optimal body mass index were shown to exhibit lower bioavailability of tacrolimus. ABCB1 1236 C>T and 2677G>T/A showed inverse association while CYP3A5*3 showed a positive association with the bioavailability of tacrolimus. Gender bias was observed in the association with ABCB1 3435 C>T polymorphism. CYP3A5*3 was shown to interact synergistically in increasing the bioavailability in combination with ABCB1 1236 TT or 2677GG genotypes. LR model showed an independent association of ABCB1 2677 G>T/A with post transplant diabetes (OR: 4.83, 95% CI: 1.22-19.03). Multifactor dimensionality reduction analysis (MDR) revealed that synergistic interactions between CYP3A5*3 and ABCB1 2677 G>T/A as the determinants of risk for post-transplant diabetes. To conclude, the ANN and MDR models explore both individual and synergistic effects of variables in modulating the bioavailability of tacrolimus and risk for post-transplant diabetes.
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Affiliation(s)
- Kalluri Thishya
- Departments of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences Hyderabad, Telangana, India
| | | | | | - Shree Bhushan Raju
- Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telanagana, India
| | - Vijay Kumar Kutala
- Departments of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences Hyderabad, Telangana, India
- * E-mail:
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22
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Woillard JB, Saint-Marcoux F, Debord J, Åsberg A. Pharmacokinetic models to assist the prescriber in choosing the best tacrolimus dose. Pharmacol Res 2018; 130:316-321. [DOI: 10.1016/j.phrs.2018.02.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 01/10/2018] [Accepted: 02/12/2018] [Indexed: 12/20/2022]
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23
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Gervasini G, García-Pino G, Vergara E, Mota-Zamorano S, García-Cerrada M, Luna E. CYP3A genotypes of donors but not those of the patients increase the risk of acute rejection in renal transplant recipients on calcineurin inhibitors: a pilot study. Eur J Clin Pharmacol 2017; 74:53-60. [DOI: 10.1007/s00228-017-2353-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 10/10/2017] [Indexed: 01/28/2023]
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Shuker N, Bouamar R, Hesselink DA, van Gelder T, Caliskan K, Manintveld OC, Balk AH, Constantinescu AA. Intrapatient Variability in Tacrolimus Exposure Does Not Predict The Development of Cardiac Allograft Vasculopathy After Heart Transplant. EXP CLIN TRANSPLANT 2017; 16:326-332. [PMID: 28969528 DOI: 10.6002/ect.2016.0366] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcomes after kidney transplant. We hypothesized that a high intrapatient variability of tacrolimus exposure after heart transplant may be associated with cardiac allograft vasculopathy as a determinant of long-term survival of heart transplant recipients. MATERIALS AND METHODS Eighty-six heart transplant recipients were included. Patients underwent coronary angiography at years 1 and 4 after transplant and were divided according to low and high intrapatient variability of tacrolimus exposure, with the median variability as cut-off. The primary outcome was the association between tacrolimus intrapatient variability and the progression of cardiac allograft vasculopathy score between years 1 and 4. Secondary outcome was this association with acute cellular rejection. RESULTS There was no significant difference in the proportion of patients with high tacrolimus intrapatient variability in the group that progressed to higher grades of cardiac allograft vasculopathy (n = 15) versus the group without progression (n = 71) at 4-year follow-up (60.0% vs 47.9%; P = .57). There was no significant difference in the proportion of patients with high tacrolimus intrapatient variability between the 58 patients with 1 or more acute cellular rejection episodes and the 28 patients without rejection (51.7% vs 46.4%; P = .82). CONCLUSIONS A high intrapatient variability in tacrolimus exposure does not appear to influence heart transplant outcomes, unlike its influence on kidney transplant function. A higher immunosuppression exposure after heart transplant, including the use of prednisone often in a combination of 3 immunosuppressive drugs, may protect against the effects of high intrapatient tacrolimus variability.
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Affiliation(s)
- Nauras Shuker
- Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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The combination of CYP3A4*22 and CYP3A5*3 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation. Pharmacogenet Genomics 2017; 27:313-322. [DOI: 10.1097/fpc.0000000000000296] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Thölking G, Gerth HU, Schuette-Nuetgen K, Reuter S. Influence of tacrolimus metabolism rate on renal function after solid organ transplantation. World J Transplant 2017; 7:26-33. [PMID: 28280692 PMCID: PMC5324025 DOI: 10.5500/wjt.v7.i1.26] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/22/2016] [Accepted: 01/14/2017] [Indexed: 02/05/2023] Open
Abstract
The calcineurin inhibitor (CNI) tacrolimus (TAC) is an integral part of the immunosuppressive regimen after solid organ transplantation. Although TAC is very effective in prevention of acute rejection episodes, its highly variable pharmacokinetic and narrow therapeutic window require frequent monitoring of drug levels and dose adjustments. TAC can cause CNI nephrotoxicity even at low blood trough levels (4-6 ng/mL). Thus, other factors besides the TAC trough level might contribute to CNI-related kidney injury. Unfortunately, TAC pharmacokinetic is determined by a whole bunch of parameters. However, for daily clinical routine a simple application strategy is needed. To address this problem, we and others have evaluated a simple calculation method in which the TAC blood trough concentration (C) is divided by the daily dose (D). Fast TAC metabolism (C/D ratio < 1.05) was identified as a potential risk factor for an inferior kidney function after transplantation. In this regard, we recently showed a strong association between fast TAC metabolism and CNI nephrotoxicity as well as BKV infection. Therefore, the TAC C/D ratio may assist transplant clinicians in a simple way to individualize the immunosuppressive regimen.
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Fan B, Qiu K, Jiang Y, Hu X, Yin H, Wang W, Ren L, Liu H, Wang W, Zhang X. Prograf produces more benefits for CYP3A5 low expression patients in early stage after kidney transplantation. Biomed Pharmacother 2017; 88:738-744. [PMID: 28157649 DOI: 10.1016/j.biopha.2017.01.101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 01/16/2017] [Accepted: 01/17/2017] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVE This study is to analyze concentration changes of the prolonged-release and shorter-acting formulation of tacrolimus in patients with different CYP3A5 genotypes after kidney transplantation. METHODS A single-factor retrospective analysis was performed in patients underwent allogeneic kidney transplantation with postoperative administration of Advagraf or Prograf in our hospital from May 2013 to June 2014. The CYP3A5 genotypes were determined, and tacrolimus trough concentrations in whole blood were measured within 28days after transplantation. The rates of acute rejection rate, chronic rejection and infection were recorded and compared after one year follow-up after surgery. RESULTS The study included 106 patients administered Advagraf (45 cases) or Prograf (61 cases). The low expression genotype of CYP3A5 was detected in 40 (37.7%) patients. A higher dose of Advagraf was required to increase the tacrolimus trough concentrations within 21days after transplantation. Moreover, a higher dose for Advagraf than Prograf was required to increase the tacrolimus trough concentrations in low expression patients. In the low expression patients, Prograf more frequently achieved the target tacrolimus trough concentrations within seven days after transplantation (five days: 7.14% vs. 84%, P=0.001; seven days: 33.33% vs. 77.78%, P=0.001). The patient and kidney graft survival rates one year after transplantation both were 100%. The estimated glomerular filtration rate showed no significant difference between different CYP3A5 phenotypes or formulations of tacrolimus (P>0.05). However, the incidence of infections was higher in the Advagraf group in low expression patients (P<0.05). CONCLUSION Tacrolimus of different formulations had different impact on patients with different CYP3A5 genotypes after kidney transplantation.
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Affiliation(s)
- Bohan Fan
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Kui Qiu
- Department of Pharmacy, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Yihang Jiang
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Xiaopeng Hu
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Hang Yin
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Wei Wang
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Liang Ren
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Hang Liu
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Wei Wang
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Xiaodong Zhang
- Department of Urology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China.
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Shuker N, Bouamar R, van Schaik RHN, Clahsen-van Groningen MC, Damman J, Baan CC, van de Wetering J, Rowshani AT, Weimar W, van Gelder T, Hesselink DA. A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype-Based With Body-Weight-Based Tacrolimus Dosing After Living Donor Kidney Transplantation. Am J Transplant 2016; 16:2085-96. [PMID: 26714287 DOI: 10.1111/ajt.13691] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Revised: 12/06/2015] [Accepted: 12/20/2015] [Indexed: 01/25/2023]
Abstract
Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.
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Affiliation(s)
- N Shuker
- Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - R Bouamar
- Department of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - R H N van Schaik
- Department of Clinical Chemistry, Erasmus Medical Centre, Rotterdam, The Netherlands
| | | | - J Damman
- Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands
| | - C C Baan
- Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - J van de Wetering
- Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - A T Rowshani
- Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - W Weimar
- Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - T van Gelder
- Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - D A Hesselink
- Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
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Tang JT, Andrews LM, van Gelder T, Shi YY, van Schaik RHN, Wang LL, Hesselink DA. Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations. Expert Opin Drug Metab Toxicol 2016; 12:555-65. [PMID: 27010623 DOI: 10.1517/17425255.2016.1170808] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. AREAS COVERED The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. EXPERT OPINION The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ~ 40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.
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Affiliation(s)
- J T Tang
- a Department of Laboratory Medicine , West China Hospital of Sichuan University , Chengdu , China.,b Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - L M Andrews
- b Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - T van Gelder
- b Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.,c Department of Internal Medicine, Division of Nephrology and Renal Transplantation , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Y Y Shi
- d Department of Nephrology , West China Hospital of Sichuan University , Chengdu , China
| | - R H N van Schaik
- e Department of Clinical Chemistry , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - L L Wang
- a Department of Laboratory Medicine , West China Hospital of Sichuan University , Chengdu , China
| | - D A Hesselink
- c Department of Internal Medicine, Division of Nephrology and Renal Transplantation , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
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Pharmacogenetic Biomarkers Predictive of the Pharmacokinetics and Pharmacodynamics of Immunosuppressive Drugs. Ther Drug Monit 2016; 38 Suppl 1:S57-69. [DOI: 10.1097/ftd.0000000000000255] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Vanhove T, Annaert P, Kuypers DRJ. Clinical determinants of calcineurin inhibitor disposition: a mechanistic review. Drug Metab Rev 2016; 48:88-112. [DOI: 10.3109/03602532.2016.1151037] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT. Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature. Clin Pharmacokinet 2016; 54:709-35. [PMID: 25860377 DOI: 10.1007/s40262-015-0267-1] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.
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Affiliation(s)
- Stefan Wolking
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Strasse 3, 72076, Tübingen, Germany
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Aouam K, Kolsi A, Kerkeni E, Ben Fredj N, Chaabane A, Monastiri K, Boughattas N. 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; 16:2045-54. [PMID: 26615671 DOI: 10.2217/pgs.15.138] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIM The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A>G and CYP3A5 6986A>G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C0 target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase. PATIENTS & METHODS We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C0 monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 promoter (rs2740574; -392A>G) and CYP3A5 (rs776746; 6986A>G) SNP genotyping was analyzed using PCR-RFLP. RESULTS Fifty-two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose-normalized C0 (C0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C0/D Tac. The mean daily doses (mg/kg) matching therapeutic C0, regardless of the CYP3A genotypes, were 0.16 ± 0.05 and 0.10 ± 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4*1B allele require higher doses to maintain the C0 in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5*1 require significant higher Tac doses, only during the early phase. CONCLUSION Our data support a critical role of the CYP3A5 6986A>G and CYP3A4 -392A>G polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug. Further studies are needed to investigate this issue.
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Affiliation(s)
- Karim Aouam
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
| | - Abdessalem Kolsi
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
| | - Emna Kerkeni
- Laboratory of Genetics, Faculty of Medicine, University of Monastir, Tunisia
| | - Nadia Ben Fredj
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
| | - Amel Chaabane
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
| | - Kamel Monastiri
- Laboratory of Genetics, Faculty of Medicine, University of Monastir, Tunisia
| | - Naceur Boughattas
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia
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Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients. Pharmacogenet Genomics 2015; 24:597-606. [PMID: 25322286 DOI: 10.1097/fpc.0000000000000095] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIM In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.g. acute rejection, diabetes mellitus) was compared between genotypes. RESULTS Fast metabolizers (CYP3A5*1/POR*28T carriers) had two-fold to three-fold higher tacrolimus dose requirements compared with slow metabolizers (CYP3A5*3/*3/CYP3A4*22 carriers) and needed significantly more time to achieve the target tacrolimus C0 of a minimum 10 ng/ml (3.3±1.7 vs. 1.34±0.75 days; P<0.0001). No differences in acute rejection incidence and time to first rejection were observed. Slow metabolizers more frequently had tacrolimus C0 above the target range early after transplantation (70 vs. 13% on day 3); however, this did not translate into a higher incidence of post-transplantation diabetes mellitus or graft dysfunction. Multivariate analyses identified the CYP3A5*1/POR*28/CYP3A4*22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year, explaining between 24-40% of its variability, whereas recipient age, hematocrit, and delayed graft function were additional nongenetic determinants of tacrolimus dose. CONCLUSION Combining the CYP3A5*1, POR*28 and CYP3A4*22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation, but without obvious clinical implications. Larger prospective studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients.
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Townamchai N, Chancharoenthana W, Vadcharavivad S, Chariyavilaskul P, Pongpirul K, Leelahavanichkul A, Watanatorn S, Avihingsanon Y, Praditpornsilpa K, Srisawat N. A Simple Novel Technique to Estimate Tacrolimus Dosages During the Early Post Kidney Transplantation Period. Transplant Proc 2015; 47:2433-8. [PMID: 26518946 DOI: 10.1016/j.transproceed.2015.08.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 08/11/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND Tacrolimus pharmacokinetics prediction by CYP3A5 genotyping is not available in many Asian resource-limited settings. Therefore, an alternative technique is needed to estimate the dose of tacrolimus perioperatively. The 12-hour level after the first dose (C12-0) is an alternative technique for estimating the dose of tacrolimus. This simple and inexpensive calculation technique can be used by any transplantation center. METHODS A prospective study on a cohort of 57 incident post-kidney transplant recipients was conducted. The whole-blood tacrolimus trough level (C12-0) was measured at 12 hours after the first dose (0.1 mg/kg) of orally administered tacrolimus during transplantation. Concomitant medications with CYP3A5 inhibitors/inducers were not allowed. Genotyping for CYP3A5 expression was carried out by reverse transcription polymerase chain reaction. The dosages and trough levels of tacrolimus at postoperative day 7 and postoperative months 1 to 3 were measured and analyzed for the dose requirements for therapeutic levels (mg/kg/d). RESULTS The doses of tacrolimus were widely diverse, ranging from 0.049 to 0.260 mg/kg/d and 0.031 to 0.298 mg/kg/d at day 7 and months 1 to 3, respectively. There were 9, 28, and 20 patients (15.8%, 49.1%, and 35.1%) with CYP3A5 *1/*1, *1/*3, and *3/*3, respectively. The CYP3A5 genotypes were significantly correlated with the target tacrolimus dose at day 7 (r(2) = 0.307) and the stable dose at months 1 to 3 (r(2) = 0.337). The C12-0 level also was significantly correlated with the dose of tacrolimus at day 7 (r(2) = 0.546) and the stable dose at months 1 to 3 (r(2) = 0.406). CONCLUSIONS There were strong correlations between the C12-0 level and the tacrolimus doses during the perioperative period at day 7 and the stable period at 1 to 3 months. Countries with limited resources for genotype testing can use the C12-0 level as an alternative to estimate the tacrolimus dose.
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Affiliation(s)
- N Townamchai
- Division of Nephrology, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
| | - W Chancharoenthana
- Division of Nephrology, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - S Vadcharavivad
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - P Chariyavilaskul
- Pharmacokinetic Research Unit, Department of Pharmacology, Chulalongkorn University, Bangkok, Thailand
| | - K Pongpirul
- Department of Preventive and Social Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - A Leelahavanichkul
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - S Watanatorn
- Division of Nephrology, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Y Avihingsanon
- Division of Nephrology, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - K Praditpornsilpa
- Division of Nephrology, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - N Srisawat
- Division of Nephrology, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
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Stefanović NZ, Cvetković TP, Veličković-Radovanović RM, Jevtović-Stoimenov TM, Vlahović PM, Stojanović IR, Pavlović DD. Pharmacogenetics may Influence Tacrolimus Daily Dose, but not Urinary Tubular Damage Markers in the Long-Term Period after Renal Transplantation. J Med Biochem 2015; 34:422-430. [PMID: 28356851 PMCID: PMC4922361 DOI: 10.1515/jomb-2015-0001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 10/05/2014] [Indexed: 11/15/2022] Open
Abstract
Background The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients. Methods The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-β-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage. Results The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients’ genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes’ activities. Conclusions Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug’s tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.
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Affiliation(s)
| | - Tatjana P Cvetković
- Institute of Biochemistry, Faculty of Medicine, University of Niš, Serbia; Clinic of Nephrology, Clinical Centre Niš, Serbia
| | | | | | | | - Ivana R Stojanović
- Institute of Biochemistry, Faculty of Medicine, University of Niš, Serbia
| | - Dušica D Pavlović
- Institute of Biochemistry, Faculty of Medicine, University of Niš, Serbia
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Vanhove T, de Jonge H, de Loor H, Verbeke K, Kuypers DRJ. Response to 'Tacrolimus pharmacokinetics after kidney transplantation--Influence of changes in haematocrit and steroid dose'. Br J Clin Pharmacol 2015; 80:1473-4. [PMID: 26235051 DOI: 10.1111/bcp.12728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 07/29/2015] [Indexed: 11/27/2022] Open
Affiliation(s)
- Thomas Vanhove
- Departments of Nephrology and Renal Transplantation, University of Leuven, Leuven, Belgium
| | - Hylke de Jonge
- Departments of Nephrology and Renal Transplantation, University of Leuven, Leuven, Belgium
| | - Henriëtte de Loor
- Laboratory of Nephrology, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
| | - Kristin Verbeke
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospitals Leuven, Leuven, Belgium
| | - Dirk R J Kuypers
- Departments of Nephrology and Renal Transplantation, University of Leuven, Leuven, Belgium
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de Jonge H, Vanhove T, de Loor H, Verbeke K, Kuypers DRJ. Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit. Br J Clin Pharmacol 2015; 80:548-59. [PMID: 26114223 DOI: 10.1111/bcp.12703] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 06/12/2015] [Accepted: 06/21/2015] [Indexed: 12/14/2022] Open
Abstract
AIMS The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo. METHODS Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes. RESULTS Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h(-1) at day 7; 17 ± 9.1 l h(-1) at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min(-1) at day 7 vs. 730 ± 344 ml min(-1) at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min(-1) for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time. CONCLUSIONS The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.
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Affiliation(s)
- Hylke de Jonge
- Departments of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Thomas Vanhove
- Departments of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Henriëtte de Loor
- Laboratory of Nephrology, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
| | - Kristin Verbeke
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospitals Leuven, Leuven, Belgium
| | - Dirk R J Kuypers
- Departments of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
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Andrews LM, Riva N, de Winter BC, Hesselink DA, de Wildt SN, Cransberg K, van Gelder T. Dosing algorithms for initiation of immunosuppressive drugs in solid organ transplant recipients. Expert Opin Drug Metab Toxicol 2015; 11:921-36. [DOI: 10.1517/17425255.2015.1033397] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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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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Medeiros M, Castañeda-Hernández G, Ross CJD, Carleton BC. Use of pharmacogenomics in pediatric renal transplant recipients. Front Genet 2015; 6:41. [PMID: 25741362 PMCID: PMC4332348 DOI: 10.3389/fgene.2015.00041] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 01/28/2015] [Indexed: 12/17/2022] Open
Abstract
Transplant recipients receive potent immunosuppressive drugs in order to prevent graft rejection. Therapeutic drug monitoring is the current approach to guide the dosing of calcineurin inhibitors, mammalian target of rapamycin inhibitors (mTORi) and mofetil mycophenolate. Target concentrations used in pediatric patients are extrapolated from adult studies. Gene polymorphisms in metabolizing enzymes and drug transporters such as cytochromes CYP3A4 and CYP3A5, UDP-glucuronosyl transferase, and P-glycoprotein are known to influence the pharmacokinetics and dose requirements of immunosuppressants. The implications of pharmacogenomics in this patient population is discussed. Genetic information can help with achieving target concentrations in the early post-transplant period, avoiding adverse drug reactions and drug-drug interactions. Evidence about genetic studies and transplant outcomes is revised.
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Affiliation(s)
- Mara Medeiros
- Laboratorio de Investigación en Nefrología y Metabolismo Mineral, Hospital Infantil de México Federico Gómez México, México ; Departamento de Farmacología, Facultad de Medicina UNAM México, México ; Pharmaceutical Outcomes Programme, Pediatrics, BC Children's Hospital, University of British Columbia Vancouver, BC, Canada
| | - Gilberto Castañeda-Hernández
- Departamento de Farmacología, Centro de Investigacion y Estudios Avanzados del Instituto Politecnico Nacional México, México
| | - Colin J D Ross
- Pharmaceutical Outcomes Programme, Pediatrics, BC Children's Hospital, University of British Columbia Vancouver, BC, Canada ; Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia Vancouver, BC, Canada ; Child and Family Research Institute, University of British Columbia Vancouver, BC, Canada
| | - Bruce C Carleton
- Pharmaceutical Outcomes Programme, Pediatrics, BC Children's Hospital, University of British Columbia Vancouver, BC, Canada ; Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia Vancouver, BC, Canada ; Child and Family Research Institute, University of British Columbia Vancouver, BC, Canada
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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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Rojas L, Neumann I, Herrero MJ, Bosó V, Reig J, Poveda JL, Megías J, Bea S, Aliño SF. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. THE PHARMACOGENOMICS JOURNAL 2014; 15:38-48. [PMID: 25201288 DOI: 10.1038/tpj.2014.38] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 03/26/2014] [Accepted: 06/04/2014] [Indexed: 12/21/2022]
Abstract
The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.
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Affiliation(s)
- L Rojas
- 1] Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile [2] Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - I Neumann
- 1] Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile [2] Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
| | - M José Herrero
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - V Bosó
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - J Reig
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - J Luis Poveda
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - J Megías
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - S Bea
- Nephrology Department, Kidney transplant Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - S F Aliño
- 1] Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain [2] Clinical Pharmacology Unit, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, Spain [3] Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
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Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients. Ther Drug Monit 2014; 36:71-9. [PMID: 24061445 DOI: 10.1097/ftd.0b013e31829da6dd] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND The P450 oxidoreductase (POR)*28 variant allele has been associated with altered cytochrome P450 3A enzyme activities. Both CYP3A5 and CYP3A4 are involved in the metabolism of calcineurin inhibitors and recent data show that POR*28 may explain part of the variability observed in tacrolimus (Tac) pharmacokinetics. The aim of this study was to investigate the impact of the POR*28 allele on Tac and cyclosporine A (CsA) immunosuppressive therapies. METHODS Kidney transplant recipients receiving either Tac (n = 184) or CsA (n = 174), participating in a prospective multicenter trial, were genotyped for POR*28, CYP3A4*22, and CYP3A5*3. RESULTS CYP3A5 expressers that were carriers of at least 1 POR*28 allele had a 16.9% decrease in dose-adjusted predose concentrations when compared CYP3A5 expressers that carried the POR*1/*1 genotype (P = 0.03), indicating an increased CYP3A5 activity for POR*28 carriers. In CYP3A5, nonexpressers carrying 2 POR*28 alleles, a 24.1% (confidence interval95% = -39.4% to -4.9%; P = 0.02) decrease in dose-adjusted predose concentrations was observed for Tac, suggesting higher CYP3A4 activity. For CsA, POR*28/*28 patients not expressing CYP3A5 and not carrying the CYP3A4*22 decrease-of-function allele showed 15% lower CsA dose-adjusted predose concentrations (P = 0.01), indicating also increased CYP3A4 activity. In both cohorts (ie, Tac and CsA), the POR*28 allele was neither associated with the incidence of delayed graft function nor with biopsy-proven acute rejection. These results were further confirmed in 2 independent cohorts. CONCLUSIONS Our results show that the POR*28 allele is associated with increased in vivo CYP3A5 activity for Tac in CYP3A5 expressers, whereas POR*28 homozygosity was associated with a significant higher CYP3A4 activity in CYP3A5 nonexpressers for both Tac and CsA.
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Kim SK, Park HJ, Seok H, Jeon HS, Lee TW, Lee SH, Moon JY, Ihm CG, Kim TH, Kim YH, Kang SW, Park SJ, Jeong KH, Chung JH. Association studies of cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene polymorphisms with acute rejection in kidney transplantation recipients. Clin Transplant 2014; 28:707-12. [PMID: 24654912 DOI: 10.1111/ctr.12369] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2014] [Indexed: 12/18/2022]
Abstract
Recent studies have shown that single-nucleotide polymorphisms (SNPs) are associated with allograft rejection in kidney transplantation recipients. We evaluated the possible association between SNPs of the cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene, and acute rejection (AR) among renal transplant patients in a Korean population. We conducted a case-control association study in 63 AR and 284 non-AR kidney transplant recipients. The SNPs of CYP2E1 were genotyped by direct sequencing. Recipient sex (p = 0.023) and the use of tacrolimus (p = 0.017) were significantly different between the two groups. The use of mycophenolate mofetil (MMF) and antibody induction therapy was significantly lower in the AR group. Multiple logistic regression models (codominant, dominant, recessive, and log-additive models) adjusted by sex and type of immunosuppressive regimens were applied to determine the odds ratios (ORs), 95% confidence intervals (CIs), and p-values. The rs2515641 of CYP2E1 showed significant differences between the AR patient group and non-AR group (p = 0.003, OR = 2.55, 95% CI = 1.37-4.75 in the codominant 1 model; p = 0.002, OR = 2.61, 95% CI = 1.43-4.77 in the dominant model; p = 0.0035, OR = 2.13, 95% CI = 1.29-3.50 in the log-additive model). The allele of the rs2515641 SNP also showed a significant association (p = 0.004, OR = 1.99, 95% CI = 1.24-3.21). This study suggests that the CYP2E1 polymorphism may be related to the development of AR in Korean kidney transplantation recipients.
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Affiliation(s)
- Su Kang Kim
- Kohwang Medical Research Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
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Murray B, Hawes E, Lee RA, Watson R, Roederer MW. Genes and beans: pharmacogenomics of renal transplant. Pharmacogenomics 2014; 14:783-98. [PMID: 23651025 DOI: 10.2217/pgs.13.68] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Advances in the management of patients after solid organ transplantation have led to dramatic decreases in rates of acute rejection, but long-term graft and patient survival have remained unchanged. Individualized therapy after transplant will ideally provide adequate immunosuppression while limiting the adverse effects of drug therapy that significantly impact graft survival. Therapeutic drug monitoring represents the best approximation of individualized drug therapy in transplant at this time; however, obtaining pharmacogenomic data in transplant patients has the potential to enhance our current practice. Polymorphisms of target genes that impact pharmacokinetics have been identified for most immunosuppressants, including tacrolimus, cyclosporine, mycophenolate, azathioprine and sirolimus. In the future, pre-emptive assessment of a patient's genetic profile may inform drug selection and provide information on specific doses that will improve efficacy and limit toxicity.
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Affiliation(s)
- Brian Murray
- Critical Care Clinical Specialist, UNC Hospitals & Clinics, 101 Manning Drive, CB #7600, Chapel Hill, NC 27599-7600, USA.
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Ogasawara K, Chitnis SD, Gohh RY, Christians U, Akhlaghi F. Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients. Clin Pharmacokinet 2014; 52:751-62. [PMID: 23633119 DOI: 10.1007/s40262-013-0069-2] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND OBJECTIVE Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus. SUBJECTS AND METHODS A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes were determined. In addition, the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (-24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. RESULTS Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose-normalized trough concentration of tacrolimus by 2.3-fold (p < 0.001) and 1.5-fold (p = 0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7 × (age/50)(-0.78) × 2.03 (CYP3A5 expressers) × 1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus. CONCLUSIONS This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.
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Affiliation(s)
- Ken Ogasawara
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 02881, USA
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Xue F, Han L, Chen Y, Xi Z, Li Q, Xu N, Xia Y, Streicher K, Zhang J, Xia Q. CYP3A5 genotypes affect tacrolimus pharmacokinetics and infectious complications in Chinese pediatric liver transplant patients. Pediatr Transplant 2014; 18:166-76. [PMID: 24438215 DOI: 10.1111/petr.12216] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/02/2013] [Indexed: 12/01/2022]
Abstract
Little information is available regarding the impact of cytochrome P450 (CYP) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty-four patients were divided according to CYP3A5 genotype (expression of *1 allele: EX and NEX) for each recipient (R) and donor (D), EX-R/EX-D (n = 21), EX-R/NEX-D (n = 8), NEX-R/EX-D (n = 8) and NEX-R/NEX-D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX-R/EX-D children compared with those who did not express CYP3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p < 0.01). CYP3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX-R/EX-D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP3A5 expression partially explains TAC dose requirement, the effect of CYP3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under- and over-immunosuppression.
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Affiliation(s)
- Feng Xue
- Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
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Hamzah S, Teh LK, Siew JSK, Ahmad G, Wong HS, Zakaria ZA, Salleh MZ. Pharmacogenotyping of CYP3A5 in predicting dose-adjusted trough levels of tacrolimus among Malaysian kidney-transplant patients. Can J Physiol Pharmacol 2014; 92:50-7. [DOI: 10.1139/cjpp-2013-0128] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Tacrolimus (FK506) is a calcineurin inhibitor with a narrow therapeutic index that exhibits large interindividual variation. Seventy-eight kidney transplant patients treated with tacrolimus were recruited to study the correlation of dose adjusted trough level (level/dose; L/D) of tacrolimus with CYP3A5 and ABCB1 genotypes, as well as the mRNA copy number of ABCB1 in blood. Patients were genotyped for ABCB1 (C1236T, G2677T/A, and C3435T) and CYP3A5 (G6986A), while ABCB1 mRNA transcript copy number was determined by absolute quantification (real-time PCR) in 46 patients. CYP3A5*3 genotypes were found to be a good predictor of tacrolimus L/D in kidney-transplant patients. Significantly higher L/D was observed among non-expressors (2.85, 95%: 2.05–3.70 (ng·mL–1)/(mg·kg–1)) as compared with the expressors (1.15, 95%: 0.95–1.80 (ng·mL–1)/(mg·kg–1)) of CYP3A5 (Mann–Whitney U test; P < 0.001). No correlation was observed between L/D and the ABCB1 genotypes. A significant inverse correlation of blood ABCB1 mRNA level with L/D was demonstrated (Spearman’s Rank Order correlation; P = 0.016, rs = –0.348). However, in multiple regression analysis, only CYP3A5*3 genotype groups were found to be significantly correlated with tacrolimus L/D (P < 0.001). These findings highlight the importance of CYP3A5*3 pharmacogenotyping among kidney-transplant patients treated with tacrolimus, and confirm the role of blood cell P-glycoprotein in influencing the L/D for tacrolimus.
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Affiliation(s)
- Sharina Hamzah
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA (UiTM), 42300 Puncak Alam, Selangor DE, Malaysia
| | - Lay Kek Teh
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA (UiTM), 42300 Puncak Alam, Selangor DE, Malaysia
| | - John Shia Kwong Siew
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA (UiTM), 42300 Puncak Alam, Selangor DE, Malaysia
| | - Ghazali Ahmad
- Department of Nephrology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Hin Seng Wong
- Department of Nephrology, Hospital Selayang, Selangor, Malaysia
| | - Zainul Amiruddin Zakaria
- Department of Biomedical Sciences, Faculty of Medicine and Health Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), 42300 Puncak Alam, Selangor DE, Malaysia
| | - Mohd Zaki Salleh
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA (UiTM), 42300 Puncak Alam, Selangor DE, Malaysia
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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: 71] [Impact Index Per Article: 5.9] [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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