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tacrolimus pharmacogenetic

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https://www.readbyqxmd.com/read/27591328/con-the-use-of-calcineurin-inhibitors-in-the-treatment-of-lupus-nephritis
#1
Maria Fernandez Nieto, David R Jayne
Lupus nephritis (LN) therapy has limited efficacy due to its toxicity, and LN patients suffer high risks of renal and cardiovascular morbidity and mortality. Calcineurin inhibitors (CNIs) have been used for over >30 years in LN treatment and are an established alternative therapy for Class V nephritis, but uncertainty remains about their role in proliferative disease or in the maintenance of remission. More recently, the combination of CNIs with mycophenolate mofetil (MMF) and glucocorticoid combination therapy, 'multitarget' therapy and the use of tacrolimus as opposed to ciclosporin has received attention...
October 2016: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/27417340/therapeutic-monitoring-of-the-immuno-modulating-drugs-in-systemic-lupus-erythematosus
#2
Chi Chiu Mok
INTRODUCTION: Despite the emergence of newer immunomodulating agents for systemic lupus erythematosus (SLE), a substantial proportion of patients still do not respond optimally. While the mechanisms for the differential responses to drug therapy are unclear, variation in drug exposure with the same dosing protocol related to pharmacogenetic and pharmacokinetic factors may contribute. This article discusses the use of therapeutic drug monitoring (TDM) to optimize therapies in SLE patients...
July 22, 2016: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/27314545/cyp3a-pharmacogenetics-and-tacrolimus-disposition-in-adult-heart-transplant-recipients
#3
Kimberly M Deininger, Anh Vu, Robert L Page, Amrut V Ambardekar, JoAnn Lindenfeld, Christina L Aquilante
BACKGROUND: Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A4*22 and CYP3A5*3 variants on tacrolimus drug disposition in adult heart transplant recipients. METHODS: The retrospective study included 76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A4*22 and CYP3A5*3, and combined genotypes were classified as follows: extensive metabolizers (EM, CYP3A4*1/*1+CYP3A5*1 carriers), intermediate metabolizers (IM, CYP3A4*1/*1+CYP3A5*3/*3, or CYP3A4*22 carriers+CYP3A5*1 carriers), and poor metabolizers (PM, CYP3A4*22 carriers+CYP3A5*3/*3)...
September 2016: Clinical Transplantation
https://www.readbyqxmd.com/read/27266721/pharmacogenetic-based-strategy-using-de-novo-tacrolimus-once-daily-after-kidney-transplantation-prospective-pilot-study
#4
Martine De Meyer, Vincent Haufroid, Nada Kanaan, Tom Darius, Antoine Buemi, Luc De Pauw, Djamila Chaïb Eddour, Pierre Wallemacq, Michel Mourad
AIM: The once daily tacrolimus formulation (Tac-OD) has been associated with better patient adherence and low variability in exposure. Patients carrying the CYP3A5*1 allele show accelerated clearance of Tac. Authors prospectively evaluate a simplified strategy for Tac-OD administration. PATIENTS & METHODS: After grafting, 151 patients were divided into four groups and received a daily dose calculated according to CYP3A5 genotypes and unchanged for the first 3 days: CYP3A5*3/*3: 0...
June 2016: Pharmacogenomics
https://www.readbyqxmd.com/read/27010623/pharmacogenetic-aspects-of-the-use-of-tacrolimus-in-renal-transplantation-recent-developments-and-ethnic-considerations
#5
J T Tang, L M Andrews, T van Gelder, Y Y Shi, R H N van Schaik, L L Wang, D A Hesselink
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...
May 2016: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/26990694/long-term-clinical-impact-of-adaptation-of-initial-tacrolimus-dosing-to-cyp3a5-genotype
#6
N Pallet, I Etienne, M Buchler, E Bailly, B Hurault de Ligny, G Choukroun, C Colosio, A Thierry, C Vigneau, B Moulin, Y Le Meur, A-E Heng, C Legendre, P Beaune, M A Loriot, E Thervet
Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years...
September 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/26714287/a-randomized-controlled-trial-comparing-the-efficacy-of-cyp3a5-genotype-based-with-body-weight-based-tacrolimus-dosing-after-living-donor-kidney-transplantation
#7
N Shuker, R Bouamar, R H N van Schaik, M C Clahsen-van Groningen, J Damman, C C Baan, J van de Wetering, A T Rowshani, W Weimar, T van Gelder, D A Hesselink
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...
July 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/26651976/influence-of-cyp3a5-polymorphism-on-the-pharmacokinetics-of-psychiatric-drugs
#8
REVIEW
Georgia Ragia, Marja-Liisa Dahl, Vangelis G Manolopoulos
BACKGROUND: The contribution of the CYP3A5 enzyme to the metabolism of clinically used drugs has been established only for a few CYP3A substrates, such as the immunosuppressant tacrolimus, while for drugs used in the field of psychiatry its role is still vague. METHODS: We herein discuss all published data on the contribution of CYP3A5 and its polymorphisms to the metabolism of antipsychotics and antidepressants that are known to be metabolized by CYP3A enzymes, as well as of carbamazepine, an antiepileptic drug used as mood stabilizer...
2016: Current Drug Metabolism
https://www.readbyqxmd.com/read/26622455/investigation-of-cyp-3a5-and-abcb1-gene-polymorphisms-in-the-long-term-following-renal-transplantation-effects-on-tacrolimus-exposure-and-kidney-function
#9
Nikola Z Stefanović, Tatjana P Cvetković, Tatjana M Jevtović-Stoimenov, Aleksandra M Ignjatović, Goran J Paunović, Radmila M Veličković
The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period...
September 2015: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/26521259/population-pharmacokinetics-and-pharmacogenetics-of-once-daily-tacrolimus-formulation-in-stable-liver-transplant-recipients
#10
D J A R Moes, S A S van der Bent, J J Swen, T van der Straaten, A Inderson, E Olofsen, H W Verspaget, H J Guchelaar, J den Hartigh, B van Hoek
PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure...
February 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/26469711/pharmacogenetic-biomarkers-predictive-of-the-pharmacokinetics-and-pharmacodynamics-of-immunosuppressive-drugs
#11
Nicolas Picard, Stein Bergan, Pierre Marquet, Teun van Gelder, Pierre Wallemacq, Dennis A Hesselink, Vincent Haufroid
In association with therapeutic drug monitoring of immunosuppressive drugs, pharmacogenetics has rapidly emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. Pharmacogenetic biomarkers are now readily available in most transplantation centers, at a limited cost and within a limited analytical time frame, which make them compatible with the clinical decision process. However, despite some evidence of clear associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several immunosuppressive drugs, pre-emptive genotyping and selection of the optimal starting dose based on the genetic background of the patient is still rarely performed in clinical practice...
April 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/26325438/influence-of-absorption-distribution-metabolism-and-excretion-genomic-variants-on-tacrolimus-sirolimus-blood-levels-and-graft-versus-host-disease-after-allogeneic-hematopoietic-cell-transplantation
#12
Samer K Khaled, Joycelynne M Palmer, Josef Herzog, Tracey Stiller, Ni-Chun Tsai, David Senitzer, Xueli Liu, Sandra H Thomas, Sepideh Shayani, Jeffrey Weitzel, Stephen J Forman, Ryotaro Nakamura
Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus-based graft-versus-host disease (GVHD) prophylaxis...
February 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/26307985/impact-of-single-nucleotide-polymorphisms-snps-on-immunosuppressive-therapy-in-lung-transplantation
#13
Jesus Ruiz, María José Herrero, Virginia Bosó, Juan Eduardo Megías, David Hervás, Jose Luis Poveda, Juan Escrivá, Amparo Pastor, Amparo Solé, Salvador Francisco Aliño
Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients)...
August 25, 2015: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/26107754/association-of-snps-with-the-efficacy-and-safety-of-immunosuppressant-therapy-after-heart-transplantation
#14
Ignacio Sánchez-Lázaro, María José Herrero, Consuelo Jordán-De Luna, Virginia Bosó, Luis Almenar, Luis Rojas, Luis Martínez-Dolz, Juan E Megías-Vericat, Luis Sendra, Antonio Miguel, José L Poveda, Salvador F Aliño
AIM: Studying the possible influence of SNPs on efficacy and safety of calcineurin inhibitors upon heart transplantation. MATERIALS & METHODS: In 60 heart transplant patients treated with tacrolimus or cyclosporine, we studied a panel of 36 SNPs correlated with a series of clinical parameters during the first post-transplantation year. RESULTS: The presence of serious infections was correlated to ABCB1 rs1128503 (p = 0.012), CC genotype reduced the probability of infections being also associated with lower blood cyclosporine concentrations...
2015: Pharmacogenomics
https://www.readbyqxmd.com/read/26005938/-pharmacogenetics-of-immunosuppressants
#15
Pier Giorgio Cojutti, Massimo Baraldo
Individualized drug therapy with immunosuppressants is an hot topic in transplantation. Therapeutic drug monitoring (TDM) is currently utilized to guide therapy, but toxic or subtherapeutic concentrations can only be identified after the drug is administered. Pharmacogenetics, by studying the relationship between a human genetic difference and drug response, holds great promises in optimizing immunosuppressive drug prescribing for solid organ transplantation.Nevertheless, a complete translation in the clinic has lagged behind,due to the overall complexity of the genetic approach, and the lack of sound evidence of identified genetic polymorphisms in ultimately explaining drug exposure...
March 2015: Giornale Italiano di Nefrologia: Organo Ufficiale Della Società Italiana di Nefrologia
https://www.readbyqxmd.com/read/25801146/clinical-pharmacogenetics-implementation-consortium-cpic-guidelines-for-cyp3a5-genotype-and-tacrolimus-dosing
#16
K A Birdwell, B Decker, J M Barbarino, J F Peterson, C M Stein, W Sadee, D Wang, A A Vinks, Y He, J J Swen, J S Leeder, Rhn van Schaik, K E Thummel, T E Klein, K E Caudle, I A M MacPhee
Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www...
July 2015: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/25781547/abcb1-mdr-1-pharmacogenetics-of-tacrolimus-in-renal-transplanted-patients-a-next-generation-sequencing-approach
#17
Beatriz Tavira, Juan Gómez, Carmen Diaz-Corte, Beatriz Suarez, Diego Coronel, Manuel Arias, Carlos López-Larrea, Sara Iglesias, Belén Alonso, Emilio Rodrigo, Eliecer Coto
BACKGROUND: A CYP3A5 gene polymorphism is the main determinant of Tacrolimus (Tac) dose requirements among renal transplanted patients. In spite of the utility of CYP3A5 genotyping to predict the Tac-dose, many patients exhibit an out of range blood Tac level and it is thus likely that other genes/polymorphisms contribute to define Tac bioavailability. To address this issue we searched for coding sequence variants in the ABCB1/MDR1 gene in renal transplanted patients treated with Tac and who had out of the range blood levels...
September 1, 2015: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/25645611/pharmacogenomics-personalizing-pediatric-heart-transplantation
#18
REVIEW
Sara L Van Driest, Steven A Webber
No abstract text is available yet for this article.
February 3, 2015: Circulation
https://www.readbyqxmd.com/read/25590378/the-functional-implications-of-common-genetic-variation-in-cyp3a5-and-abcb1-in-human-proximal-tubule-cells
#19
Noël Knops, Lambertus P van den Heuvel, Rosalinde Masereeuw, Inge Bongaers, Henriëtte de Loor, Elena Levtchenko, Dirk Kuypers
BACKGROUND: Calcineurin inhibitors (CNIs) are the primary immunosuppressive drugs used in solid organ transplantation but are associated with the development of histological lesions leading to kidney failure. CNIs are metabolized by CYP3A and excreted by not only P-glycoprotein (P-gp) (ABCB1) in the gut and liver, but also by proximal tubule cells (PTCs) in the kidney. Multiple studies have demonstrated the importance of genetic variation in CYP3A5 and ABCB1 for CNI disposition and nephrotoxicity...
March 2, 2015: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/25416736/choosing-the-right-dose-of-tacrolimus
#20
REVIEW
Pauline Lancia, Evelyne Jacqz-Aigrain, Wei Zhao
Choosing the right dose of tacrolimus 'adapted to each individual patient' is a central question after transplantation. The pharmacokinetic behaviour of tacrolimus in paediatric patients is significantly influenced by clinical factors growth and maturation, as well as genetic factors. Large interindividual variability and narrow therapeutic index make dosage individualisation mandatory in children. CYP3A5 expressers require a 1.8-fold higher tacrolimus dose than non-expressers. A visual patient-tailored dosing chart, taking into consideration the child's weight, recent haematocrit level and CYP3A5 genotype, was developed based on a population pharmacokinetic-pharmacogenetic model, and can be used routinely to individualise tacrolimus starting dose...
April 2015: Archives of Disease in Childhood
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