Pub Date : 2025-02-01Epub Date: 2024-12-24DOI: 10.1097/FTD.0000000000001288
Smita Pattanaik, Caroline Monchaud
Abstract: The concept of pharmacokinetic (PK) boosting of calcineurin inhibitors (CNI) emerged after the FDA approval of cyclosporine-A. Several studies followed, and the proof of concept was well established by the late 1990s. This also continued for the next blockbuster immunosuppressant, tacrolimus. The driver for such research was an endeavor to save costs, as both drugs were expensive due to patent protection. Two CYP inhibitors, ketoconazole and diltiazem, have been extensively studied in this context and continue to be prescribed off-label along with the CNI. It has been observed that using ketoconazole reduces the dose requirement of tacrolimus by about 50% and 30% with diltiazem, which is in conformity with their pharmacological actions. Off-label co-prescription of these drugs with CNI is often encountered in low and middle-income countries. The foremost reason cited is economic. This article collates the evidence from the clinical studies that evaluate the PK-boosting effects of CNI and also reviews the gaps in the current evidence base. The current knowledge prevents the transplant community from making meaningful inferences about the risks and benefits of such strategies. Although the PK-boosting strategy can lead to serious adverse events, emerging evidence suggests that it may be advantageous for individuals with high CNI dose requirements. Hence, PK boosting may be an unmet need in the therapeutics of CNI. Nevertheless, there are several unanswered questions surrounding such use, and therefore, this merits testing in well-designed clinical studies. Moreover, drugs with better safer profiles and a history of successful PK boosting may be considered for evaluation with CNI.
{"title":"Pharmacokinetic Boosting of Calcineurin Inhibitors in Transplantation: Pros, Cons, and Perspectives.","authors":"Smita Pattanaik, Caroline Monchaud","doi":"10.1097/FTD.0000000000001288","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001288","url":null,"abstract":"<p><strong>Abstract: </strong>The concept of pharmacokinetic (PK) boosting of calcineurin inhibitors (CNI) emerged after the FDA approval of cyclosporine-A. Several studies followed, and the proof of concept was well established by the late 1990s. This also continued for the next blockbuster immunosuppressant, tacrolimus. The driver for such research was an endeavor to save costs, as both drugs were expensive due to patent protection. Two CYP inhibitors, ketoconazole and diltiazem, have been extensively studied in this context and continue to be prescribed off-label along with the CNI. It has been observed that using ketoconazole reduces the dose requirement of tacrolimus by about 50% and 30% with diltiazem, which is in conformity with their pharmacological actions. Off-label co-prescription of these drugs with CNI is often encountered in low and middle-income countries. The foremost reason cited is economic. This article collates the evidence from the clinical studies that evaluate the PK-boosting effects of CNI and also reviews the gaps in the current evidence base. The current knowledge prevents the transplant community from making meaningful inferences about the risks and benefits of such strategies. Although the PK-boosting strategy can lead to serious adverse events, emerging evidence suggests that it may be advantageous for individuals with high CNI dose requirements. Hence, PK boosting may be an unmet need in the therapeutics of CNI. Nevertheless, there are several unanswered questions surrounding such use, and therefore, this merits testing in well-designed clinical studies. Moreover, drugs with better safer profiles and a history of successful PK boosting may be considered for evaluation with CNI.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 1","pages":"118-140"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-11-19DOI: 10.1097/FTD.0000000000001281
Nils Tore Vethe, Anders Åsberg, Stein Bergan, Ida Robertsen, Karsten Midtvedt
Background: Home-based hospital services are becoming increasingly popular, and the addition of remote outpatient appointments after kidney transplantation facilitates more practical and closer follow-up. In this context, finger-prick self-sampling is an important aspect of monitoring of immunosuppressants and biomarkers. Nevertheless, several issues must be addressed to ensure the feasibility and quality when implementing microsampling in clinical practice. We summarize our experiences and opinions in this field.
Methods: This article is based on the authors' experience regarding the laboratory and clinical implementation of finger-prick self-sampling in kidney transplant recipients. The referenced literature is related to the authors' knowledge in this field.
Results: We present considerations for the selection of relevant analytes, key characteristics of selected volumetric sampling tools (Mitra and Capitainer), and the associated sampling pitfalls. In addition, we address the requirements for patients performing finger-prick sampling, appropriate design of methods and workflow, critical points for validation, and aspects related to logistics and digital solutions.
Conclusions: Volumetric finger-prick self-sampling is suitable for monitoring immunosuppressants and certain biomarkers that are relevant to outpatient follow-up after kidney transplantation. We believe that a carefully designed system for the entire workflow, including patient training, will be beneficial in enabling a safe experience for transplant recipients, as well as ensuring overall efficiency and adequate quality. In the future, a combination of immunosuppressants with a wide range of biomarkers has significant potential for use in at-home self-sampling after kidney transplantation.
{"title":"Implementation of Volumetric Finger-Prick Self-Sampling for Therapeutic Drug Monitoring of Immunosuppressants After Kidney Transplantation: Lessons Learned From the Practice.","authors":"Nils Tore Vethe, Anders Åsberg, Stein Bergan, Ida Robertsen, Karsten Midtvedt","doi":"10.1097/FTD.0000000000001281","DOIUrl":"10.1097/FTD.0000000000001281","url":null,"abstract":"<p><strong>Background: </strong>Home-based hospital services are becoming increasingly popular, and the addition of remote outpatient appointments after kidney transplantation facilitates more practical and closer follow-up. In this context, finger-prick self-sampling is an important aspect of monitoring of immunosuppressants and biomarkers. Nevertheless, several issues must be addressed to ensure the feasibility and quality when implementing microsampling in clinical practice. We summarize our experiences and opinions in this field.</p><p><strong>Methods: </strong>This article is based on the authors' experience regarding the laboratory and clinical implementation of finger-prick self-sampling in kidney transplant recipients. The referenced literature is related to the authors' knowledge in this field.</p><p><strong>Results: </strong>We present considerations for the selection of relevant analytes, key characteristics of selected volumetric sampling tools (Mitra and Capitainer), and the associated sampling pitfalls. In addition, we address the requirements for patients performing finger-prick sampling, appropriate design of methods and workflow, critical points for validation, and aspects related to logistics and digital solutions.</p><p><strong>Conclusions: </strong>Volumetric finger-prick self-sampling is suitable for monitoring immunosuppressants and certain biomarkers that are relevant to outpatient follow-up after kidney transplantation. We believe that a carefully designed system for the entire workflow, including patient training, will be beneficial in enabling a safe experience for transplant recipients, as well as ensuring overall efficiency and adequate quality. In the future, a combination of immunosuppressants with a wide range of biomarkers has significant potential for use in at-home self-sampling after kidney transplantation.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"98-104"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-09-25DOI: 10.1097/FTD.0000000000001250
Satohiro Masuda, Florian Lemaitre, Markus J Barten, Stein Bergan, Maria Shipkova, Teun van Gelder, Sander Vinks, Eberhard Wieland, Kirsten Bornemann-Kolatzki, Mercè Brunet, Brenda de Winter, Maja-Theresa Dieterlen, Laure Elens, Taihei Ito, Kamisha Johnson-Davis, Pawel K Kunicki, Roland Lawson, Nuria Lloberas, Pierre Marquet, Olga Millan, Tomoyuki Mizuno, Dirk Jan A R Moes, Ofelia Noceti, Michael Oellerich, Smita Pattanaik, Tomasz Pawinski, Christoph Seger, Ron van Schaik, Raman Venkataramanan, Phil Walson, Jean-Baptiste Woillard, Loralie J Langman
Abstract: The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.
{"title":"Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.","authors":"Satohiro Masuda, Florian Lemaitre, Markus J Barten, Stein Bergan, Maria Shipkova, Teun van Gelder, Sander Vinks, Eberhard Wieland, Kirsten Bornemann-Kolatzki, Mercè Brunet, Brenda de Winter, Maja-Theresa Dieterlen, Laure Elens, Taihei Ito, Kamisha Johnson-Davis, Pawel K Kunicki, Roland Lawson, Nuria Lloberas, Pierre Marquet, Olga Millan, Tomoyuki Mizuno, Dirk Jan A R Moes, Ofelia Noceti, Michael Oellerich, Smita Pattanaik, Tomasz Pawinski, Christoph Seger, Ron van Schaik, Raman Venkataramanan, Phil Walson, Jean-Baptiste Woillard, Loralie J Langman","doi":"10.1097/FTD.0000000000001250","DOIUrl":"10.1097/FTD.0000000000001250","url":null,"abstract":"<p><strong>Abstract: </strong>The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"4-31"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-10-24DOI: 10.1097/FTD.0000000000001273
Julia O Nascimento, Edlaine R Costa, Rita Estrela, Fernanda L Moreira
Background: Methods for measuring drug levels in the body are crucial for improving therapeutic drug monitoring (TDM) and personalized medicine. In solid-organ transplants, TDM is essential for the management of immunosuppressive drugs to avoid toxicity and organ rejection. Everolimus is a commonly used immunosuppressant with a small range of safe doses; therefore, it is important to adjust the dose according to each patient's needs. Therefore, reliable methods are required to accurately measure everolimus levels. This study aims to conduct a comprehensive and updated narrative review of chromatographic bioanalytical methods for everolimus quantification.
Methods: The authors searched for original research articles published between 2013 and 2023 in Scopus and PubMed and found 295 articles after removing duplicates. Based on their titles and summaries, 30 articles were selected for a detailed review and 25 articles were included in the final analysis.
Results: Among the 25 studies, 16 used protein precipitation, mainly with methanol, to prepare the samples, 12 used high-performance liquid chromatography, 11 used ultra-performance liquid chromatography, and 2 used both. Almost all the studies (24 of 25) used tandem mass spectrometry for detection, whereas only 1 used ultraviolet.
Conclusions: This comprehensive review of bioanalytical methods for measuring everolimus using chromatography is a useful resource for researchers developing bioanalytical methods for TDM applications. Future trends in everolimus measurement include achieving lower detection limits, owing to the trend of reducing drug doses in therapy by improving sample extraction techniques and using more sensitive methods.
{"title":"A Narrative Review of Chromatographic Bioanalytical Methods for Quantifying Everolimus in Therapeutic Drug Monitoring Applications.","authors":"Julia O Nascimento, Edlaine R Costa, Rita Estrela, Fernanda L Moreira","doi":"10.1097/FTD.0000000000001273","DOIUrl":"10.1097/FTD.0000000000001273","url":null,"abstract":"<p><strong>Background: </strong>Methods for measuring drug levels in the body are crucial for improving therapeutic drug monitoring (TDM) and personalized medicine. In solid-organ transplants, TDM is essential for the management of immunosuppressive drugs to avoid toxicity and organ rejection. Everolimus is a commonly used immunosuppressant with a small range of safe doses; therefore, it is important to adjust the dose according to each patient's needs. Therefore, reliable methods are required to accurately measure everolimus levels. This study aims to conduct a comprehensive and updated narrative review of chromatographic bioanalytical methods for everolimus quantification.</p><p><strong>Methods: </strong>The authors searched for original research articles published between 2013 and 2023 in Scopus and PubMed and found 295 articles after removing duplicates. Based on their titles and summaries, 30 articles were selected for a detailed review and 25 articles were included in the final analysis.</p><p><strong>Results: </strong>Among the 25 studies, 16 used protein precipitation, mainly with methanol, to prepare the samples, 12 used high-performance liquid chromatography, 11 used ultra-performance liquid chromatography, and 2 used both. Almost all the studies (24 of 25) used tandem mass spectrometry for detection, whereas only 1 used ultraviolet.</p><p><strong>Conclusions: </strong>This comprehensive review of bioanalytical methods for measuring everolimus using chromatography is a useful resource for researchers developing bioanalytical methods for TDM applications. Future trends in everolimus measurement include achieving lower detection limits, owing to the trend of reducing drug doses in therapy by improving sample extraction techniques and using more sensitive methods.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"49-63"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-11-05DOI: 10.1097/FTD.0000000000001276
Olga Millán, Judit Julian, Mercè Brunet
Abstract: The use of noninvasive biomarkers may reduce the need for biopsy and guide immunosuppression adjustments during transplantation. The scientific community in solid organ transplantation currently considers that chemokines, T- and B-cell immunophenotypes, and gene expression, among other molecular biomarkers, have great potential as diagnostic and predictive biomarkers for graft evolution; however, in clinical practice, few valid early biomarkers have emerged. This review focuses on the most relevant scientific advances in this field in the last 5 years regarding the role of 3 biomarkers: miRNAs, chemokines, and ddcf-DNA, in both adult and pediatric populations. An update was provided on the scores based on the combination of these biomarkers. The most-featured articles were identified through a literature search of the PubMed database. This review provides a comprehensive analysis of the potential clinical applications of these biomarkers in the diagnosis and prediction of graft outcomes and discusses the reasons why none have been implemented in clinical practice to date. Translating these biomarkers into routine clinical practice and combining them with pharmacogenetics and pharmacokinetic monitoring is challenging; however, it is the key to present/future individualized immunosuppressive therapies. It is essential that they be shown to be applicable and robust in real-life patient conditions and properly evaluate their added value when combined with the standard-of-care factor monitoring for graft clinical assessment. Partnership strategies among scientists, academic institutions, consortia, including expert working groups and scientific societies, and pharmaceutical and/or biotechnology companies should promote the development of prospective, randomized, multicenter intervention studies for adequate clinical validation of these biomarkers and their monitoring frequency, and their commercialization to make them available to transplant physicians.
摘要:非侵入性生物标志物的使用可减少活组织检查的需要,并指导移植过程中免疫抑制的调整。目前,实体器官移植领域的科学界认为,趋化因子、T 细胞和 B 细胞免疫表型以及基因表达等分子生物标志物作为诊断和预测移植物演变的生物标志物具有巨大的潜力;然而,在临床实践中,有效的早期生物标志物却寥寥无几。本综述重点介绍了过去五年中该领域最相关的科学进展,涉及 miRNA、趋化因子和 ddcf-DNA 这三种生物标志物在成人和儿童人群中的作用。根据这些生物标志物的组合对评分进行了更新。通过对 PubMed 数据库进行文献检索,确定了最具特色的文章。本综述全面分析了这些生物标志物在诊断和预测移植物预后方面的潜在临床应用,并讨论了迄今为止尚未在临床实践中应用的原因。将这些生物标志物转化为常规临床实践并与药物遗传学和药代动力学监测相结合具有挑战性;然而,这是目前/未来个体化免疫抑制疗法的关键。至关重要的是,必须证明它们在实际患者病情中的适用性和稳健性,并适当评估它们与移植物临床评估的标准护理因子监测相结合后的附加值。科学家、学术机构、联合体(包括专家工作组和科学协会)以及制药和/或生物技术公司之间的合作战略应促进前瞻性、随机、多中心干预研究的发展,以便对这些生物标志物及其监测频率进行充分的临床验证,并促进其商业化,使移植医生能够获得这些生物标志物。
{"title":"miRNAs, dd-cf-DNA, and Chemokines as Potential Noninvasive Biomarkers for the Assessment of Clinical Graft Evolution and Personalized Immunosuppression Requirement in Solid Organ Transplantation.","authors":"Olga Millán, Judit Julian, Mercè Brunet","doi":"10.1097/FTD.0000000000001276","DOIUrl":"10.1097/FTD.0000000000001276","url":null,"abstract":"<p><strong>Abstract: </strong>The use of noninvasive biomarkers may reduce the need for biopsy and guide immunosuppression adjustments during transplantation. The scientific community in solid organ transplantation currently considers that chemokines, T- and B-cell immunophenotypes, and gene expression, among other molecular biomarkers, have great potential as diagnostic and predictive biomarkers for graft evolution; however, in clinical practice, few valid early biomarkers have emerged. This review focuses on the most relevant scientific advances in this field in the last 5 years regarding the role of 3 biomarkers: miRNAs, chemokines, and ddcf-DNA, in both adult and pediatric populations. An update was provided on the scores based on the combination of these biomarkers. The most-featured articles were identified through a literature search of the PubMed database. This review provides a comprehensive analysis of the potential clinical applications of these biomarkers in the diagnosis and prediction of graft outcomes and discusses the reasons why none have been implemented in clinical practice to date. Translating these biomarkers into routine clinical practice and combining them with pharmacogenetics and pharmacokinetic monitoring is challenging; however, it is the key to present/future individualized immunosuppressive therapies. It is essential that they be shown to be applicable and robust in real-life patient conditions and properly evaluate their added value when combined with the standard-of-care factor monitoring for graft clinical assessment. Partnership strategies among scientists, academic institutions, consortia, including expert working groups and scientific societies, and pharmaceutical and/or biotechnology companies should promote the development of prospective, randomized, multicenter intervention studies for adequate clinical validation of these biomarkers and their monitoring frequency, and their commercialization to make them available to transplant physicians.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"77-97"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-03DOI: 10.1097/FTD.0000000000001287
Caroline Monchaud, Antoine Humeau, Sabrina Crépin, Lama Kawsarani, Claire Villeneuve, Isabelle Etienne, Jean-Philippe Rerolle, Pierre Marquet
Abstract: In transplantation, the association of tacrolimus exposure with efficacy is better known than with adverse effects. The ExpoTac study explored the relationships between tacrolimus exposure and adverse events (AEs) in kidney transplant patients who benefited from at least 3 measurements of tacrolimus area under the curve (AUC) within 2 years of transplantation. The relationships between tacrolimus AUC, trough concentration C 0 , peak concentration C max , and AEs were explored using univariate analysis and Cox models in 386 patients (1281 sets of exposure biomarkers). Headaches and renal impairment potentially induced by tacrolimus were associated with significantly lower mean dose-standardized exposure biomarkers and a higher proportion of C max values above the median. Patients with tremor displayed significantly higher mean AUC 0-24 (343 ± 79 versus 308 ± 63 hours·mcg/L, P = 0.041). Cox analysis revealed a significant association between (1) the time to the first headache report and mean C max , mean AUC 0-24 , and the proportion of C max values above the median (hazard ratios [95% confidence interval] = 0.237 [0.007-0.538]; 7.499 [1.508-29.713]; 5.055 [1.577-17.137]) and (2) the time to first renal impairment report and the proportion of C 0 values above the median (0.401 [0.098-0.681]). Refining AUC, C max , and C 0 upper limits would help to refine tacrolimus therapeutic ranges and limit the risks of AEs after kidney transplantation.
摘要:在移植中,他克莫司暴露与疗效的关系比与不良反应的关系更广为人知。ExpoTac研究探讨了他克莫司暴露与肾移植患者不良事件(ae)之间的关系,这些患者在移植后2年内至少接受了3次他克莫司曲线下面积(AUC)测量。采用单因素分析和Cox模型对386例患者(1281组暴露生物标志物)他克莫司AUC、谷浓度C0、峰浓度Cmax与ae之间的关系进行了探讨。他克莫司可能引起的头痛和肾脏损害与平均剂量标准化暴露生物标志物显著降低和Cmax值高于中位数的比例较高相关。震颤患者的平均AUC0-24(343±79比308±63小时·mcg/L, P = 0.041)明显高于震颤患者。Cox分析显示:(1)首次头痛报告的时间与平均Cmax、平均AUC0-24和Cmax值高于中位数的比例存在显著相关(风险比[95%置信区间]= 0.237 [0.007-0.538];7.499 (1.508 - -29.713);5.055[1.577-17.137])和(2)首次报告肾功能损害的时间和C0值高于中位数的比例(0.401[0.098-0.681])。细化AUC、Cmax和C0上限将有助于细化他克莫司的治疗范围,限制肾移植后不良反应的风险。
{"title":"Relationships Between Tacrolimus Exposure and Adverse Events in Renal Transplant Patients: The ExpoTac Study.","authors":"Caroline Monchaud, Antoine Humeau, Sabrina Crépin, Lama Kawsarani, Claire Villeneuve, Isabelle Etienne, Jean-Philippe Rerolle, Pierre Marquet","doi":"10.1097/FTD.0000000000001287","DOIUrl":"10.1097/FTD.0000000000001287","url":null,"abstract":"<p><strong>Abstract: </strong>In transplantation, the association of tacrolimus exposure with efficacy is better known than with adverse effects. The ExpoTac study explored the relationships between tacrolimus exposure and adverse events (AEs) in kidney transplant patients who benefited from at least 3 measurements of tacrolimus area under the curve (AUC) within 2 years of transplantation. The relationships between tacrolimus AUC, trough concentration C 0 , peak concentration C max , and AEs were explored using univariate analysis and Cox models in 386 patients (1281 sets of exposure biomarkers). Headaches and renal impairment potentially induced by tacrolimus were associated with significantly lower mean dose-standardized exposure biomarkers and a higher proportion of C max values above the median. Patients with tremor displayed significantly higher mean AUC 0-24 (343 ± 79 versus 308 ± 63 hours·mcg/L, P = 0.041). Cox analysis revealed a significant association between (1) the time to the first headache report and mean C max , mean AUC 0-24 , and the proportion of C max values above the median (hazard ratios [95% confidence interval] = 0.237 [0.007-0.538]; 7.499 [1.508-29.713]; 5.055 [1.577-17.137]) and (2) the time to first renal impairment report and the proportion of C 0 values above the median (0.401 [0.098-0.681]). Refining AUC, C max , and C 0 upper limits would help to refine tacrolimus therapeutic ranges and limit the risks of AEs after kidney transplantation.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"152-160"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-11-20DOI: 10.1097/FTD.0000000000001286
Maria Shipkova, Florian Lemaitre
{"title":"Therapeutic Drug Monitoring of Immunosuppressive Drugs: A Field Constantly in Motion.","authors":"Maria Shipkova, Florian Lemaitre","doi":"10.1097/FTD.0000000000001286","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001286","url":null,"abstract":"","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 1","pages":"1-3"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-10DOI: 10.1097/FTD.0000000000001289
Nuria Lloberas, Anna Vidal-Alabró, Helena Colom
Abstract: Different polymorphisms in genes encoding metabolizing enzymes and drug transporters have been associated with tacrolimus pharmacokinetics. In particular, studies on CYP3A4 and CYP3A5, and their combined cluster have demonstrated their significance in adjusting tacrolimus dosing to minimize under- and overexposure thereby increasing the proportion of patients who achieve tacrolimus therapeutic target. Many factors influence the pharmacokinetics of tacrolimus, contributing to inter-patient variability affecting individual dosing requirements. On the other hand, the growing use of population pharmacokinetic models in solid organ transplantation, including different tacrolimus formulations, has facilitated the integration of pharmacogenetic data and other variables into algorithms to easier implement the personalized dose adjustment in transplant centers. The future of personalized medicine in transplantation lies in implementing these models in clinical practice, with pharmacogenetics as a key factor to account for the high inter-patient variability in tacrolimus exposure. To date, three clinical trials have validated the clinical application of these approaches. The aim of this review is to provide an overview of the current studies regarding the different population pharmacokinetic including pharmacogenetics and those translated to the clinical practice for individualizing tacrolimus dose adjustment in kidney transplantation.
{"title":"Customizing Tacrolimus Dosing in Kidney Transplantation: Focus on Pharmacogenetics.","authors":"Nuria Lloberas, Anna Vidal-Alabró, Helena Colom","doi":"10.1097/FTD.0000000000001289","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001289","url":null,"abstract":"<p><strong>Abstract: </strong>Different polymorphisms in genes encoding metabolizing enzymes and drug transporters have been associated with tacrolimus pharmacokinetics. In particular, studies on CYP3A4 and CYP3A5, and their combined cluster have demonstrated their significance in adjusting tacrolimus dosing to minimize under- and overexposure thereby increasing the proportion of patients who achieve tacrolimus therapeutic target. Many factors influence the pharmacokinetics of tacrolimus, contributing to inter-patient variability affecting individual dosing requirements. On the other hand, the growing use of population pharmacokinetic models in solid organ transplantation, including different tacrolimus formulations, has facilitated the integration of pharmacogenetic data and other variables into algorithms to easier implement the personalized dose adjustment in transplant centers. The future of personalized medicine in transplantation lies in implementing these models in clinical practice, with pharmacogenetics as a key factor to account for the high inter-patient variability in tacrolimus exposure. To date, three clinical trials have validated the clinical application of these approaches. The aim of this review is to provide an overview of the current studies regarding the different population pharmacokinetic including pharmacogenetics and those translated to the clinical practice for individualizing tacrolimus dose adjustment in kidney transplantation.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 1","pages":"141-151"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-11-20DOI: 10.1097/FTD.0000000000001275
Gretchen N de Graav, Suwasin Udomkarnjananun, Carla C Baan, Marlies E J Reinders, Joke I Roodnat, Brenda C M de Winter, Dennis A Hesselink
Purpose: In this review, the authors summarized the latest developments in costimulatory blockade to prevent rejection after solid organ transplantation (SOT) and discussed possibilities for future research and the need for therapeutic drug monitoring (TDM) of these agents.
Methods: Studies about costimulatory blockers in SOT in humans or animal transplant models in the past decade (2014-2024) were systematically reviewed in PubMed, European Union clinical trials (EudraCT), and ClinicalTrials.gov .
Results: Seventy-five registered clinical trials and 58 published articles were found on costimulation blockade of the CD28-CD80/86, CD40-CD40L, and OX40-OX40L pathways. Belatacept, an antagonist of the CD28-CD80/86 pathway, is the only approved costimulatory agent in SOT, hence accounting for most of the research. Other identified costimulatory blocking agents included abatacept and CD28 antagonists tegoprubart, dazodalibep, and TNX-1500. Although tegoprubart was unsuccessful in pancreas transplantation in nonhuman primates, trials in human kidney transplantation are underway. Dazodalibep trials faced recruitment challenges. TNX-1500 was unsuccessful in animal studies and is currently not pursued in humans. After discontinuation of iscalimab (CD40-CD154 pathway antagonist) in SOT, the alternatives, bleselumab and KPL404, showed promising results in kidney transplantation and cardiac xenotransplantation. Studies on secondary costimulatory pathway antagonists, such as OX40-OX40L, have only used animal models. Despite the low interindividual variability in pharmacokinetics (PK) in all studied agents, TDM could be useful for optimizing dosing in PK/pharmacodynamic (PD) studies.
Conclusions: The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents.
目的:在这篇综述中,作者总结了成本刺激阻断剂在预防实体器官移植(SOT)后排斥反应方面的最新进展,并讨论了未来研究的可能性以及对这些药物进行治疗药物监测(TDM)的必要性:方法:在PubMed、欧盟临床试验(EudraCT)和ClinicalTrials.gov.Results.中系统回顾了过去十年(2014-2024年)在人体或动物移植模型中使用成本刺激阻断剂治疗SOT的研究:结果:共发现75项注册临床试验和58篇已发表文章,内容涉及CD28-CD80/86、CD40-CD40L和OX40-OX40L途径的成本刺激阻断。贝拉替塞(Belatacept)是 CD28-CD80/86 通路的拮抗剂,也是唯一获准用于 SOT 的成本刺激药物,因此占据了大部分研究内容。其他已确定的成本刺激阻断剂包括阿巴他赛普特和 CD28 拮抗剂 tegoprubart、dazodalibep 和 TNX-1500。虽然 Tegoprubart 在非人灵长类的胰腺移植中没有取得成功,但在人类肾脏移植中的试验正在进行中。Dazodalibep试验面临招募困难。TNX-1500 在动物实验中未取得成功,目前也未用于人体。在 SOT 中停止使用异卡利单抗(CD40-CD154 通路拮抗剂)后,替代药物 bleselumab 和 KPL404 在肾移植和心脏异种移植中显示出良好的效果。关于次级激动通路拮抗剂(如 OX40-OX40L)的研究仅使用了动物模型。尽管所有研究药物的药代动力学(PK)个体间变异性较低,但TDM可用于优化PK/药效学(PD)研究中的剂量:结论:与标准治疗相比,成本刺激阻滞剂在 SOT 中的常规使用因疗效问题而受到阻碍。成本刺激抑制剂可与不含降钙素酶抑制剂的治疗方案相结合。未来对成本刺激剂和个性化药物的 PK/药效学研究可能会为这些药物的 TDM 提供依据。
{"title":"New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review.","authors":"Gretchen N de Graav, Suwasin Udomkarnjananun, Carla C Baan, Marlies E J Reinders, Joke I Roodnat, Brenda C M de Winter, Dennis A Hesselink","doi":"10.1097/FTD.0000000000001275","DOIUrl":"10.1097/FTD.0000000000001275","url":null,"abstract":"<p><strong>Purpose: </strong>In this review, the authors summarized the latest developments in costimulatory blockade to prevent rejection after solid organ transplantation (SOT) and discussed possibilities for future research and the need for therapeutic drug monitoring (TDM) of these agents.</p><p><strong>Methods: </strong>Studies about costimulatory blockers in SOT in humans or animal transplant models in the past decade (2014-2024) were systematically reviewed in PubMed, European Union clinical trials (EudraCT), and ClinicalTrials.gov .</p><p><strong>Results: </strong>Seventy-five registered clinical trials and 58 published articles were found on costimulation blockade of the CD28-CD80/86, CD40-CD40L, and OX40-OX40L pathways. Belatacept, an antagonist of the CD28-CD80/86 pathway, is the only approved costimulatory agent in SOT, hence accounting for most of the research. Other identified costimulatory blocking agents included abatacept and CD28 antagonists tegoprubart, dazodalibep, and TNX-1500. Although tegoprubart was unsuccessful in pancreas transplantation in nonhuman primates, trials in human kidney transplantation are underway. Dazodalibep trials faced recruitment challenges. TNX-1500 was unsuccessful in animal studies and is currently not pursued in humans. After discontinuation of iscalimab (CD40-CD154 pathway antagonist) in SOT, the alternatives, bleselumab and KPL404, showed promising results in kidney transplantation and cardiac xenotransplantation. Studies on secondary costimulatory pathway antagonists, such as OX40-OX40L, have only used animal models. Despite the low interindividual variability in pharmacokinetics (PK) in all studied agents, TDM could be useful for optimizing dosing in PK/pharmacodynamic (PD) studies.</p><p><strong>Conclusions: </strong>The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"64-76"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-11-07DOI: 10.1097/FTD.0000000000001274
Amelia R Cossart, Nicole M Isbel, Scott B Campbell, Brett McWhinney, Christine E Staatz
Background: Therapeutic monitoring is routinely performed to ensure tacrolimus whole-blood concentrations fall within a predefined target. Despite this, patients still experience inefficacy and toxicity that could be related to variability in free (unbound) tacrolimus exposure. Therefore, the aim of this study was to compare tacrolimus-free plasma (C u ), total plasma (C p ), and whole-blood (C wb ) concentrations in adult kidney transplant recipients and to characterize tacrolimus disposition across different matrices.
Methods: Twelve-hour concentration-time profiling was performed in 15 recipients, allowing simultaneous measurement of C u , C p , and C wb . Pharmacokinetic parameters were estimated using noncompartmental analysis. The relationship between C wb and C p were examined using a capacity-limited binding model, incorporating the hematocrit fraction ( fHCT ) to estimate maximum binding concentration ( Bmax ) and dissociation constant ( Kd ). The relationship between C p and C u was evaluated using a linear binding model to estimate the nonspecific binding parameter ( Nplasma ). Nonlinear regression analysis was used to obtain estimates of Bmax , Kd , and Nplasma .
Results: A total of 195 paired C wb , C p , and C u values were collected. The median ratios of C wb :C p , C p :C u , and C wb :C u were 9:1, 20:1, and 138:1, respectively. Variability in free plasma exposure was large; free trough values ranged from 8 to 51 ng/L and free area-under-the-concentration-time-curve values ranged from 424 to 7160 ng·h/L. Median (range) estimates of Bmax , Kd , and Nplasma were 90.4 µg/L (22.4-752.5 µg/L), 2.36 µg/L (0-69.2 µg/L), and 0.05 (0.035-0.085), respectively. The interindividual variability (CV%) in binding parameters was considerable ( Bmax 117.2%; Nplasma 32.5%).
Conclusions: Large variability was observed in tacrolimus-free plasma exposure and binding parameters. Future research to characterize the relationship between tacrolimus C u and patient outcomes may be of benefit.
{"title":"Examining Whole Blood, Total and Free Plasma Tacrolimus in Elderly Kidney Transplant Recipients.","authors":"Amelia R Cossart, Nicole M Isbel, Scott B Campbell, Brett McWhinney, Christine E Staatz","doi":"10.1097/FTD.0000000000001274","DOIUrl":"10.1097/FTD.0000000000001274","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic monitoring is routinely performed to ensure tacrolimus whole-blood concentrations fall within a predefined target. Despite this, patients still experience inefficacy and toxicity that could be related to variability in free (unbound) tacrolimus exposure. Therefore, the aim of this study was to compare tacrolimus-free plasma (C u ), total plasma (C p ), and whole-blood (C wb ) concentrations in adult kidney transplant recipients and to characterize tacrolimus disposition across different matrices.</p><p><strong>Methods: </strong>Twelve-hour concentration-time profiling was performed in 15 recipients, allowing simultaneous measurement of C u , C p , and C wb . Pharmacokinetic parameters were estimated using noncompartmental analysis. The relationship between C wb and C p were examined using a capacity-limited binding model, incorporating the hematocrit fraction ( fHCT ) to estimate maximum binding concentration ( Bmax ) and dissociation constant ( Kd ). The relationship between C p and C u was evaluated using a linear binding model to estimate the nonspecific binding parameter ( Nplasma ). Nonlinear regression analysis was used to obtain estimates of Bmax , Kd , and Nplasma .</p><p><strong>Results: </strong>A total of 195 paired C wb , C p , and C u values were collected. The median ratios of C wb :C p , C p :C u , and C wb :C u were 9:1, 20:1, and 138:1, respectively. Variability in free plasma exposure was large; free trough values ranged from 8 to 51 ng/L and free area-under-the-concentration-time-curve values ranged from 424 to 7160 ng·h/L. Median (range) estimates of Bmax , Kd , and Nplasma were 90.4 µg/L (22.4-752.5 µg/L), 2.36 µg/L (0-69.2 µg/L), and 0.05 (0.035-0.085), respectively. The interindividual variability (CV%) in binding parameters was considerable ( Bmax 117.2%; Nplasma 32.5%).</p><p><strong>Conclusions: </strong>Large variability was observed in tacrolimus-free plasma exposure and binding parameters. Future research to characterize the relationship between tacrolimus C u and patient outcomes may be of benefit.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 1","pages":"161-168"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}