Pharmacogenetics of tacrolimus: from bench to bedside?
Farmacogenética del tacrolimus: ¿del laboratorio al paciente?
a Servicio de Genética Molecular, Hospital Universitario Central de Asturias, Oviedo,
b Servicio de Nefrología, Hospital Universitario Central de Asturias. Departamento de Medicina, Universidad de Oviedo,
c Servicio de Nefrología, Hospital Universitario Central de Asturias, Oviedo,
d Servicio de Nefrología, Hospital Universitario Central de Asturias. Fundación Renal Iñigo Álvarez de Toledo, Madrid,
e Servicio de Genética Molecular, Hospital Universitario Central de Asturias, Oviedo. Departamento de Medicina, Universidad de Oviedo. Fundación Renal Iñigo Álvarez de Toledo, Madrid,
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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "11" "paginaFinal" => "17" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Beatriz Tavira, Carmen Díaz-Corte, Diego Coronel, Francisco Ortega, Eliecer Coto" "autores" => array:5 [ 0 => array:3 [ "nombre" => "Beatriz" "apellidos" => "Tavira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "Carmen" "apellidos" => "Díaz-Corte" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 2 => array:3 [ "nombre" => "Diego" "apellidos" => "Coronel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 3 => array:3 [ "nombre" => "Francisco" "apellidos" => "Ortega" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] ] ] 4 => array:3 [ "nombre" => "Eliecer" "apellidos" => "Coto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "affe" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Servicio de Genética Molecular, Hospital Universitario Central de Asturias, Oviedo, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Central de Asturias. Departamento de Medicina, Universidad de Oviedo, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Central de Asturias, Oviedo, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Central de Asturias. Fundación Renal Iñigo Álvarez de Toledo, Madrid, " "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Servicio de Genética Molecular, Hospital Universitario Central de Asturias, Oviedo. Departamento de Medicina, Universidad de Oviedo. Fundación Renal Iñigo Álvarez de Toledo, Madrid, " "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "affe" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Farmacogenética del tacrolimus: ¿del laboratorio al paciente?" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12267_16025_54601_en_t112267.jpg" "Alto" => 736 "Ancho" => 2216 "Tamanyo" => 299690 ] ] "descripcion" => array:1 [ "en" => "Daily dose of tacrolimus (median and range) according to CYP3A5 genotype in three series of kidney transplants" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The goal of immunosuppressive therapy is to prevent graft rejection. For this purpose drugs acting by different routes on the alloimmune response are administered, to achieve the highest degree of immunosuppression while minimising toxicity and other adverse effects, especially the development of tumours and infections.<span class="elsevierStyleSup">1</span> The recommended immunosuppressive therapy is an initial ‘induction’ therapy with antibodies (monoclonal or polyclonal), directed at preventing early rejection, and reduced doses of other immunosuppressives, especially calcineurin inhibitors, and maintenance immunosuppression with three drugs: Calcineurin inhibitors, such as tacrolimus or cyclosporine A, an inhibitor of purine synthesis (mycophenolate mofetil [MMF]) and steroids.<span class="elsevierStyleSup">2</span> Other immunosuppressive agents such as mTOR (mammalian rapamycin receptor) inhibitors (sirolimus and everolimus), although not usually used from the beginning, make it possible to use different combinations of immunosuppressants over time.</p><p class="elsevierStylePara">For most drugs each patient receives an initial dose based on variables such as weight and age. If drug blood levels can be measured, the dose may be adjusted to a blood value within an acceptable range. With regards to immunosuppressive drugs, a dose that is too low could cause organ rejection, and a dose that is too high could cause toxicity. Gene variations (mutations and polymorphisms) that encode proteins involved in drug metabolism may condition blood concentration of the pharmacologically active ingredient. Proteins encoded by these pharmacogenetically relevant genes may act at intestinal absorption level (thus affecting the amount of drug absorbed into the bloodstream) or liver, resulting in inactive or therapeutically active molecules. Finally, they can modify the drug or its metabolites to facilitate their elimination. For most genes involved in these processes there are polymorphisms that determine more or less active forms of proteins, so that, based on the corresponding genotypes, it would be possible to include each patient in a group with a better/worse therapeutic response. In this review we analyse the pharmacogenetics of tacrolimus, discussing the pros and cons of choosing a dose based on the patient's genotype.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">TACROLIMUS: MECHANISM OF ACTION, </span><span class="elsevierStyleBold">PHARMACOKINETICS AND PHARMACODYNAMICS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Tacrolimus (FK-506) is an inhibitor of calcineurin, a phosphoprotein that promotes transcription of genes involved in growth and differentiation of CD4+ T lymphocytes. When tacrolimus binds to its intracellular target, there is inhibition of transcription of genes such as interleukin-2.<span class="elsevierStyleSup">3</span>This immunosuppressant is characterised by its pharmacokinetic variability (interindividual) and its reduced therapeutic window.<span class="elsevierStyleSup">4</span> Therefore, continuous dose monitoring is required during the first weeks after transplantation in order to achieve adequate blood levels to prevent rejection (too low) or nephrotoxicity (too high).<span class="elsevierStyleSup">5,6</span> Although rapidly absorbed (in the intestine), its oral bioavailability is very low: of the total dose the patient receives only 25% would reach the blood stream. Maximum blood concentration is achieved within one to three hours after administration. Administration, either in two divided doses (Prograf ®, Astellas ®) or a single daily dose in the case of an extended release form (Advagraf ®) should be administered within 24 hours after transplantation, although depending on the donor’s features there may be differences between the centres, both in administration regimes and doses, as also combinations with other immunosuppressants. In the case of renal transplantation, the Symphony study recommends an initial oral dose of tacrolimus in the range of 0.10-0.30 mg/kg/day, depending on donor and recipient characteristics and associated immunosuppressive medication.<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">In the intestine, tacrolimus is a substrate for P-glycoprotein (Pgp) (also known as MDR-1 -multidrug resistance 1-), encoded by the ABCB1gene.<span class="elsevierStyleSup">8-10</span>This protein is found in the membrane of enterocytes and regulates the passage of substances from the interior of the cell into the extracellular space based on an adenosine triphosphate (ATP) mechanism. Once in the blood stream, tacrolimus reaches the liver where it is metabolised by CYP3A family cytochrome P450 reductases, primarily CYP3A5 and CYP3A4.<span class="elsevierStyleSup">11</span> Finally, its metabolites are excreted in urine and bile. The narrow therapeutic margin and large pharmacokinetic and pharmacodynamic variability between individuals make it necessary to measure tacrolimus blood levels and those of its metabolites to adjust the dose to achieve an appropriate circulating concentration.<span class="elsevierStyleSup">12</span> There are various measuring methods based on the use of antibodies (ELISA) or mass spectrometry. Monitoring trough levels of tacrolimus (C<span class="elsevierStyleInf">0</span>) is critical during the first days after transplant and is performed immediately before each administration. In the case of renal transplant, the Symphony study recommends that C<span class="elsevierStyleInf">0</span> levels in whole blood values should be between 5 and 20ng/ml during the first weeks after transplant, and between 3 and 12ng/ml when the patient changes to maintenance therapy.<span class="elsevierStyleSup">7</span> Monitoring and dose adjustment should be performed when immunosuppressive regimen changes are introduced, or changes in the dosage form, or after administration of other drugs that could interfere with absorption and/or metabolism (such as clopidogrel and simvastatin). Dose modifications are also necessary when nephrotoxicity is suspected.<span class="elsevierStyleSup">13,14</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">PHARMACOGENETICS OF TACROLIMUS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">The main determinant of interindividual variability in the dose of tacrolimus is the activity of cytochrome P450-3A5, encoded by CYP3A5 gene. Of all the polymorphisms of this gene, a change in a single nucleotide (SNP), known as CYP3A5*3 (SNP rs776746), is the main regulator of the optimum dose.<span class="elsevierStyleSup">15-19</span> This variant is in intron 3 of the CYP3A5 gene and affects pre-mRNA processing, so that there is not a perfect splicing between exons 3 and 4. The resulting mRNA will have an abnormal sequence, which is unstable and will be eliminated by the cell, so that it fails to synthesise protein.<span class="elsevierStyleSup">20 21</span> Consequently, carriers of two copies (homozygous) of the CYP3A5*3 allele do not have the protein (non-expressers), in contrast to carriers of at least one copy of the normal allele (designated <span class="elsevierStyleItalic">CYP3A5*1</span>).<span class="elsevierStyleSup">22-26</span> In summary, <span class="elsevierStyleItalic">CYP3A5*3</span> would make it possible to classify patients according to phenotype as “slow metabolisers” (homozygous <span class="elsevierStyleItalic">CYP3A5*3*3</span>), “intermediate metabolisers” or “fast metabolisers” (heterozygous <span class="elsevierStyleItalic">CYP3A5*1*3</span> and homozygous <span class="elsevierStyleItalic">CYP3A5*1*1</span>, respectively). The latter would require higher doses to achieve target levels of tacrolimus (Table 1).<span class="elsevierStyleSup">24-26</span> Other gene variants might be involved in the metabolism of tacrolimus, although the results obtained to date are not as conclusive as those seen with CYP3A5*3.<span class="elsevierStyleSup">27-30</span> Differences in allele frequencies of CYP3A5 gene between ethnic groups could explain the increased dose requirement in African Americans: while about 80 % of Caucasians are slow metabolisers (homozygous for the CYP3A5*3 allele), most black subjects are homozygous CYP3A5 *1*1 (fast metabolisers ).<span class="elsevierStyleSup">31.32</span>These genetic differences could also explain the increased risk of rejection and nephrotoxicity among Afro-Americans.<span class="elsevierStyleSup">33</span></p><p class="elsevierStylePara">About 40 % of tacrolimus administered to a patient is metabolised by P450-3A4. Variants of gene CYP3A4 have been found that could affect the activity of this cytochrome and, therefore, basal drug levels/doses. In the case of tacrolimus CYP3A4*1B polymorphism (SNP rs2740574) in the promoter region of the gene (-392 A> G), perhaps resulting in higher protein levels, has been associated with a requirement for greater drug doses.<span class="elsevierStyleSup">22,34,35 </span>In addition, some variants have recently been described that could affect tacrolimus metabolism, such as <span class="elsevierStyleItalic">CYP3A4*22</span> polymorphism.<span class="elsevierStyleSup">36,37</span> However, other studies do not support a significant effect of this variant of CYP3A4 on doses.<span class="elsevierStyleSup">38,39</span> When assessing these discrepancies it is necessary to be aware that most carriers of CYP3A4*22 allele in turn are homozygous for CYP3A5*3 allele, which makes it difficult to quantify its effect on fast metabolisers for CYP3A5.<span class="elsevierStyleSup">39</span></p><p class="elsevierStylePara">ABCB1 gene encodes PgP, a protein that is expressed in many cell types and tissues and regulates intestinal absorption of many drugs. A relationship has been described between C3435T polymorphism (SNP rs1045642) within exon 26 of the gene and intestinal expression of this glycoprotein. Thus, this (and other polymorphisms) could condition dosage requirements for several drugs.<span class="elsevierStyleSup">40, 41</span> In the case of tacrolimus several studies found a significant relationship between dose requirement and C3435T genotype polymorphism.<span class="elsevierStyleSup">17, 28.42</span> However, this effect has not been confirmed by others, nor does it affect the dosage level in our patients.<span class="elsevierStyleSup">17,22,28,42-44</span> The expression of PgP in renal cells could condition the amount of tacrolimus reaching their interior and, therefore, toxicity levels. In this respect, a relationship has been described between donor C3435T genotype and the risk of nephrotoxicity.<span class="elsevierStyleSup">45</span> Although this study would open up a new pharmacogenetic pathway in renal transplant, it is based on a small number of patients, and should be confirmed in other populations.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CLINICAL APPLICATION OF TACROLIMUS PHARMACOGENETICS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The initial dose of tacrolimus was determined by variables such as patient age, weight or race.<span class="elsevierStyleSup">7,46,47</span> Some authors have proposed algorithms based on different variables to calculate the initial dose, including CYP3A5 genotype, which should be determined before transplant. In theory, the inclusion of genotype could reduce the number of dose adjustments and the time necessary to reach the desired blood level. For several drugs, the choice of a dose based on genotype is already a recommendation from the Food and Drug Administration and other agencies. In the case of tacrolimus, for the medical community to accept pharmacogenetics as a prescription criterion, patient genotype should provide significant advantages with regards to current procedures: for example, reducing the percentage of rejection or other adverse events, fewer modification of post-transplant doses; savings by reducing pharmaceutical expenditure or hospital stay, etc.   However, so far no studies have clearly demonstrated the advantages of giving a variable initial dose by genotype compared to the current method of a predetermined dose.</p><p class="elsevierStylePara">To demonstrate these advantages, a group of patients would have to be treated using an initial dose based on genotype to compare the results with a group of similar characteristics (age, sex, immunosuppressive scheme) to which tacrolimus is administered following traditional guidelines. This approach has been used in a study performed on 236 renal transplant patients divided into two groups: 120 patients (control group) received 0.2 mg/kg/day and 116 patients (adapted dose group) received a dose according to CYP3A5 genotype: 0.15 mg/kg/day in the case of slow metabolisers (homozygous for <span class="elsevierStyleItalic">CYP3A5*3*3, </span>n = 90) and 0.30 mg/kg/day in the case of fast metabolisers (<span class="elsevierStyleItalic">CYP3A5*1 carriers, </span>n = 26).<span class="elsevierStyleSup">48</span> However, patients began to receive tacrolimus as from post-transplant day 7 (not from the first day), and were kept under low induction therapy with basiliximab (Simulect<span class="elsevierStyleSup">®</span>; Novartis, Basel, Switzerland) or a<span class="elsevierStyleItalic">nti</span>-thymocyte <span class="elsevierStyleItalic">globulin</span> (Thymoglobulin<span class="elsevierStyleSup">®</span>; Genzyme, Cambridge, MA) during that week. The two groups were compared based on the percentage of cases with a C0 value in the 10-15ng/l range after six oral doses of tacrolimus, time to achieve that range, number of dose modifications to achieve that range, number dialysis sessions to organ function, incidence of acute rejection (biopsy-proven ), loss of organ and death.<span class="elsevierStyleSup">48</span> The study concluded that after three days of treatment with tacrolimus there were a greater percentage of patients achieving target value C<span class="elsevierStyleInf">0</span> (43.2% vs. 29.1%, <span class="elsevierStyleItalic">P</span>=.03) in the adapted dose group, and these patients also required fewer dose modifications. However, the incidence of acute rejection or renal function values were similar between groups (Table 2). The sample size would be sufficient to achieve a statistical power of 80%.</p><p class="elsevierStylePara">Since measuring levels and adjusting the daily dose would make it possible for most patients to achieve target blood levels within the first two weeks after transplant, nephrologists may see little use in dose by genotype in the absence of other advantages. Since the study performed by Thervet et al. included patients treated with induction therapy and high doses of MMF, it is not surprising that there were no differences in the rate of acute rejection and other clinical variables. Therefore, it would be necessary to evaluate the role of dosage according to genotype in patients without induction therapy and administering tacrolimus immediately after transplant, instead of waiting for a week.<span class="elsevierStyleSup">49</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSIONS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">While the role of CYP3A5 genotype as a determinant of the dose of tacrolimus to administer is indisputable, the usefulness of giving an initial dose based on genotype may depend on greater benefits than the mere reduction in the number of dose modifications. More trials are necessary to demonstrate that administration of adapted doses reduces nephrotoxicity and rejection, or saves money due to lower requirements for induction therapy or shortens hospitalisation times.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">KEY CONCEPTS</span></p><p class="elsevierStylePara"> </p><li>Interindividual differences in the dose of tacrolimus are determined by a polymorphism of CYP3A5 gene.</li><li>CYP3A5 subjects, slow metabolisers, (80 % of Caucasians ) require lower doses. </li><li>Administration of an initial dose of tacrolimus based on CYP3A5 genotype could reduce the time and number of dose modifications necessary to achieve the target blood levels.</li><li>However, it is still necessary to determine whether this would reduce (among other variables) toxicity and rejection rates, the need for induction therapy or the expense of hospitalisation, among others advantages. </li><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">ACKNOWLEDGEMENTS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Study financed by the Renal Research Network of the Carlos III Institute of Health (RD12/0021/0012; RD12/0021/0018).</p><p class="elsevierStylePara"><a href="grande/12267_16025_54601_en_t112267.jpg" class="elsevierStyleCrossRefs"><img src="12267_16025_54601_en_t112267.jpg" alt="Daily dose of tacrolimus (median and range) according to CYP3A5 genotype in three series of kidney transplants"></img></a></p><p class="elsevierStylePara">Table 1. Daily dose of tacrolimus (median and range) according to CYP3A5 genotype in three series of kidney transplants</p><p class="elsevierStylePara"><a href="grande/12267_16025_54602_en_t212267.jpg" class="elsevierStyleCrossRefs"><img src="12267_16025_54602_en_t212267.jpg" alt="Summary of the study performed by Thervet et al.48"></img></a></p><p class="elsevierStylePara">Table 2. Summary of the study performed by Thervet et al.48</p>" "pdfFichero" => "P1-E565-S4487-A12267-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439041" "palabras" => array:1 [ 0 => "Trasplante renal" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439043" "palabras" => array:1 [ 0 => "Farmacogenética" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439045" "palabras" => array:1 [ 0 => "Citocromo P450" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439047" "palabras" => array:1 [ 0 => "Tacrolimus" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439049" "palabras" => array:1 [ 0 => "Farmacocinética" ] ] ] "en" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439042" "palabras" => array:1 [ 0 => "renal transplant" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439044" "palabras" => array:1 [ 0 => "Pharmacogenetics" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439046" "palabras" => array:1 [ 0 => "Cytochrome P450" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439048" "palabras" => array:1 [ 0 => "Tacrolimus" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439050" "palabras" => array:1 [ 0 => "Pharmacokinetics" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">El tacrolimus (Tac) es un inmunosupresor ampliamente usado para prevenir el rechazo en el trasplante renal. Los pacientes reciben una dosis inicial estándar y se miden los niveles sanguíneos, con ajuste de la dosis hasta alcanzar una concentración dentro del rango aceptado. Existe una gran variabilidad interindividual en las dosis necesarias para alcanzar ese nivel diana en sangre, y muchos pacientes requieren varias modificaciones de la dosis hasta alcanzarlo. Uno de los principales determinantes de estas diferencias es un polimorfismo del gen <span class="elsevierStyleItalic">CYP3A5</span> que determina que alrededor del 80 % de los caucásicos sean metabolizadores lentos y requieran dosis menores que los metabolizadores rápidos. Se ha propuesto que los pacientes trasplantados reciban dosis iniciales de Tac con base en el genotipo <span class="elsevierStyleItalic">CYP3A5</span>. Para que este procedimiento fuese aceptado por los clínicos, deberían demostrarse sus ventajas frente al procedimiento actual, más allá de un menor tiempo para alcanzar la dosis óptima. Por ejemplo, menor tasa de nefrotoxicidad y rechazo o menor coste por necesitar, entre otros, menos modificaciones de la dosis de Tac y menos terapia de inducción con anticuerpos.</p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">Tacrolimus (FK-506) is an immunosuppressant widely used to prevent kidney transplant rejection. Patients receive an initial standard dose and tacrolimus levels are measured in blood. If necessary, the dose is adjusted to reach a blood concentration within the accepted range. There is great interindividual variability in the dose required to achieve the target blood level, and many patients require multiple modifications of the dose to reach the range. One of the main determinants of these differences is a <span class="elsevierStyleItalic">CYP3A5</span> gene polymorphism that determines that about 80% of Caucasians are poor metabolisers and require lower doses compared to the extensive metabolisers. It has been proposed that transplanted patients could receive an initial Tacrolimus dose based on the <span class="elsevierStyleItalic">CYP3A5</span> genotype. This could reduce the time to achieve the optimal blood level, reducing the number of dose modifications. However, to be accepted by clinicians and translated to the clinical practice this adapted dose procedure should give additional advantages such as a significant reduction of the rates of nephrotoxicity and rejection, or a lower cost due to less dose modifications of Tacrolimus and less antibody induction therapy<span class="elsevierStyleBold">.</span></p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12267_16025_54601_en_t112267.jpg" "Alto" => 736 "Ancho" => 2216 "Tamanyo" => 299690 ] ] "descripcion" => array:1 [ "en" => "Daily dose of tacrolimus (median and range) according to CYP3A5 genotype in three series of kidney transplants" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12267_16025_54602_en_t212267.jpg" "Alto" => 1577 "Ancho" => 2173 "Tamanyo" => 573816 ] ] "descripcion" => array:1 [ "en" => "Summary of the study performed by Thervet et al.48" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:49 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Halloran F. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 12 | 6 | 18 |
| 2024 October | 73 | 59 | 132 |
| 2024 September | 87 | 52 | 139 |
| 2024 August | 74 | 81 | 155 |
| 2024 July | 86 | 72 | 158 |
| 2024 June | 80 | 58 | 138 |
| 2024 May | 95 | 52 | 147 |
| 2024 April | 85 | 66 | 151 |
| 2024 March | 77 | 55 | 132 |
| 2024 February | 58 | 57 | 115 |
| 2024 January | 57 | 29 | 86 |
| 2023 December | 48 | 43 | 91 |
| 2023 November | 100 | 74 | 174 |
| 2023 October | 95 | 78 | 173 |
| 2023 September | 79 | 64 | 143 |
| 2023 August | 78 | 52 | 130 |
| 2023 July | 103 | 51 | 154 |
| 2023 June | 159 | 36 | 195 |
| 2023 May | 114 | 57 | 171 |
| 2023 April | 69 | 29 | 98 |
| 2023 March | 94 | 37 | 131 |
| 2023 February | 59 | 25 | 84 |
| 2023 January | 94 | 34 | 128 |
| 2022 December | 78 | 49 | 127 |
| 2022 November | 79 | 41 | 120 |
| 2022 October | 92 | 70 | 162 |
| 2022 September | 66 | 66 | 132 |
| 2022 August | 80 | 55 | 135 |
| 2022 July | 48 | 66 | 114 |
| 2022 June | 62 | 62 | 124 |
| 2022 May | 82 | 52 | 134 |
| 2022 April | 72 | 60 | 132 |
| 2022 March | 73 | 64 | 137 |
| 2022 February | 86 | 61 | 147 |
| 2022 January | 150 | 41 | 191 |
| 2021 December | 96 | 57 | 153 |
| 2021 November | 58 | 50 | 108 |
| 2021 October | 79 | 62 | 141 |
| 2021 September | 55 | 51 | 106 |
| 2021 August | 83 | 62 | 145 |
| 2021 July | 83 | 40 | 123 |
| 2021 June | 37 | 31 | 68 |
| 2021 May | 46 | 50 | 96 |
| 2021 April | 117 | 79 | 196 |
| 2021 March | 77 | 62 | 139 |
| 2021 February | 91 | 18 | 109 |
| 2021 January | 54 | 13 | 67 |
| 2020 December | 63 | 41 | 104 |
| 2020 November | 45 | 12 | 57 |
| 2020 October | 54 | 19 | 73 |
| 2020 September | 51 | 21 | 72 |
| 2020 August | 56 | 14 | 70 |
| 2020 July | 75 | 26 | 101 |
| 2020 June | 77 | 22 | 99 |
| 2020 May | 69 | 26 | 95 |
| 2020 April | 61 | 14 | 75 |
| 2020 March | 91 | 21 | 112 |
| 2020 February | 91 | 26 | 117 |
| 2020 January | 112 | 25 | 137 |
| 2019 December | 118 | 19 | 137 |
| 2019 November | 97 | 38 | 135 |
| 2019 October | 85 | 12 | 97 |
| 2019 September | 65 | 21 | 86 |
| 2019 August | 63 | 26 | 89 |
| 2019 July | 49 | 24 | 73 |
| 2019 June | 55 | 23 | 78 |
| 2019 May | 68 | 15 | 83 |
| 2019 April | 118 | 56 | 174 |
| 2019 March | 57 | 34 | 91 |
| 2019 February | 33 | 21 | 54 |
| 2019 January | 59 | 20 | 79 |
| 2018 December | 148 | 61 | 209 |
| 2018 November | 208 | 27 | 235 |
| 2018 October | 136 | 28 | 164 |
| 2018 September | 269 | 27 | 296 |
| 2018 August | 159 | 16 | 175 |
| 2018 July | 153 | 20 | 173 |
| 2018 June | 156 | 16 | 172 |
| 2018 May | 126 | 10 | 136 |
| 2018 April | 92 | 16 | 108 |
| 2018 March | 132 | 17 | 149 |
| 2018 February | 103 | 17 | 120 |
| 2018 January | 90 | 18 | 108 |
| 2017 December | 99 | 11 | 110 |
| 2017 November | 108 | 20 | 128 |
| 2017 October | 70 | 18 | 88 |
| 2017 September | 108 | 12 | 120 |
| 2017 August | 119 | 19 | 138 |
| 2017 July | 85 | 15 | 100 |
| 2017 June | 108 | 12 | 120 |
| 2017 May | 135 | 19 | 154 |
| 2017 April | 105 | 14 | 119 |
| 2017 March | 121 | 15 | 136 |
| 2017 February | 224 | 17 | 241 |
| 2017 January | 81 | 26 | 107 |
| 2016 December | 112 | 14 | 126 |
| 2016 November | 144 | 26 | 170 |
| 2016 October | 268 | 20 | 288 |
| 2016 September | 435 | 10 | 445 |
| 2016 August | 426 | 20 | 446 |
| 2016 July | 323 | 21 | 344 |
| 2016 June | 231 | 0 | 231 |
| 2016 May | 206 | 0 | 206 |
| 2016 April | 171 | 0 | 171 |
| 2016 March | 169 | 0 | 169 |
| 2016 February | 169 | 0 | 169 |
| 2016 January | 160 | 0 | 160 |
| 2015 December | 157 | 0 | 157 |
| 2015 November | 120 | 0 | 120 |
| 2015 October | 148 | 0 | 148 |
| 2015 September | 111 | 0 | 111 |
| 2015 August | 80 | 0 | 80 |
| 2015 July | 107 | 0 | 107 |
| 2015 June | 68 | 0 | 68 |
| 2015 May | 84 | 0 | 84 |
| 2015 April | 16 | 0 | 16 |
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