Herramientas para un ajuste de dosis de tacrolimus más personalizado en el seguimiento de los pacientes con transplante renal. Fenotipo metabolizador según polimorfismos genéticos del CYP3A vs. el cociente concentración-dosis
Anna Vidal-Alabró , Helena Colom , Pere Fontova , Gema Cerezo , Edoardo Melilli , Núria Montero , Ana Coloma , Anna Manonellas , Alexandre Favà , Josep M. Cruzado , Joan Torras , Josep M. Grinyó , Núria Lloberas
{"title":"Herramientas para un ajuste de dosis de tacrolimus más personalizado en el seguimiento de los pacientes con transplante renal. Fenotipo metabolizador según polimorfismos genéticos del CYP3A vs. el cociente concentración-dosis","authors":"Anna Vidal-Alabró , Helena Colom , Pere Fontova , Gema Cerezo , Edoardo Melilli , Núria Montero , Ana Coloma , Anna Manonellas , Alexandre Favà , Josep M. Cruzado , Joan Torras , Josep M. Grinyó , Núria Lloberas","doi":"10.1016/j.nefro.2022.12.005","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and justification</h3><p>The strategy of the concentration–dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile.</p></div><div><h3>Materials and methods</h3><p>Four hundred and twenty-five kidney transplant patients who received Tac as immunosuppressive treatment have been included. The concentration/dose ratio (C/D) was used to divided patients in terciles and classify them according to their Tac metabolism rate (fast, intermediate, and slow). Based on CYP3A4 and A5 polymorphisms, patients were classified into three metabolizer groups: fast (<em>CYP3A5*1</em> and <em>CYP34A*1/*1</em> carriers), intermediate (<em>CYP3A5*3/3</em> and <em>CYP3A4*1/*1</em>) and slow (<em>CYP3A5*3/*3</em> and <em>CYP3A4*22</em> carriers).</p></div><div><h3>Results</h3><p>When comparing patients included in each metabolizer group according to C/D ratio, 47% (65/139) of the fast metabolizers, 85% (125/146) of the intermediate and only 12% (17/140) of the slow also fitted in the homonym genotype group. Statistically lower Tac concentrations were observed in the fast metabolizers group and higher Tac concentrations in the slow metabolizers when compared with the intermediate group both in C/D ratio and polymorphisms criteria. High metabolizers required approximately 60% more Tac doses than intermediates throughout follow-up, while poor metabolizers required approximately 20% fewer doses than intermediates. Fast metabolizers classified by both criteria presented a higher percentage of times with sub-therapeutic blood Tac concentration values.</p></div><div><h3>Conclusion</h3><p>Determination of the metabolizer phenotype according to CYP polymorphisms or the C/D ratio allows patients to be distinguished according to their exposure to Tac. Probably the combination of both classification criteria would be a good tool for managing Tac dosage for transplant patients.</p></div>","PeriodicalId":18997,"journal":{"name":"Nefrologia","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0211699522002004/pdfft?md5=3426efe7c94d9341a8551d9c29021e41&pid=1-s2.0-S0211699522002004-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nefrologia","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0211699522002004","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background and justification
The strategy of the concentration–dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile.
Materials and methods
Four hundred and twenty-five kidney transplant patients who received Tac as immunosuppressive treatment have been included. The concentration/dose ratio (C/D) was used to divided patients in terciles and classify them according to their Tac metabolism rate (fast, intermediate, and slow). Based on CYP3A4 and A5 polymorphisms, patients were classified into three metabolizer groups: fast (CYP3A5*1 and CYP34A*1/*1 carriers), intermediate (CYP3A5*3/3 and CYP3A4*1/*1) and slow (CYP3A5*3/*3 and CYP3A4*22 carriers).
Results
When comparing patients included in each metabolizer group according to C/D ratio, 47% (65/139) of the fast metabolizers, 85% (125/146) of the intermediate and only 12% (17/140) of the slow also fitted in the homonym genotype group. Statistically lower Tac concentrations were observed in the fast metabolizers group and higher Tac concentrations in the slow metabolizers when compared with the intermediate group both in C/D ratio and polymorphisms criteria. High metabolizers required approximately 60% more Tac doses than intermediates throughout follow-up, while poor metabolizers required approximately 20% fewer doses than intermediates. Fast metabolizers classified by both criteria presented a higher percentage of times with sub-therapeutic blood Tac concentration values.
Conclusion
Determination of the metabolizer phenotype according to CYP polymorphisms or the C/D ratio allows patients to be distinguished according to their exposure to Tac. Probably the combination of both classification criteria would be a good tool for managing Tac dosage for transplant patients.
期刊介绍:
Nefrología is the official publication of the Spanish Society of Nephrology. The Journal publishes articles on basic or clinical research relating to nephrology, arterial hypertension, dialysis and kidney transplants. It is governed by the peer review system and all original papers are subject to internal assessment and external reviews. The journal accepts submissions of articles in English and in Spanish languages.