Falsely Increased Blood Tacrolimus Concentrations Using the ACMIA Assay Due to Circulating Endogenous Antibodies in a Liver Transplant Recipient: A Tentative Approach to Obtaining Reliable Results

Hermida, Jesús; Tutor, J. Carlos

doi:10.1097/ftd.0b013e31819c6d5c

Cited by 45 publications

(22 citation statements)

References 14 publications

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“…The simplified and standardized sample processing of a panel of drugs saves time, reagents, and labor expenses. The analytical specificity of MS-based immunosuppressant assays is also superior to that of existing immunoassays, which can overestimate the concentration of these medications because of the variable cross-reactivity with immunosuppressant metabolites (32)(33)(34). Lastly, there is now one FDA-approved MS tacrolimus assay (WatersMassTrak®) and several commercially available MS kits with IVD (in vitro diagnostic)-CE certification for the measurement of immunosuppressants (ChromsystemsMassTox®, Recipe-ClinMass®, and Waters-MassTrak®), which make MS-based assays more attractive for smaller laboratories with less expertise (35 ).…”

Section: Advantages Of Msmentioning

confidence: 97%

Effective Use of Mass Spectrometry in the Clinical Laboratory

2016

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BACKGROUND:Historically the success of mass spectrometry in the clinical laboratory has focused on drugs of abuse confirmations, newborn screening, and steroid analysis. Clinical applications of mass spectrometry continue to expand, and mass spectrometry is now being used in almost all areas of laboratory medicine.CONTENT: A brief background of the evolution of mass spectrometry in the clinical laboratory is provided with a discussion of future applications. Prominent examples of mass spectrometry are covered to illustrate how it has improved the practice of medicine and enabled physicians to provide better patient care. With increasing economic pressures and decreasing laboratory test reimbursement, mass spectrometry testing has been shown to provide cost-effective solutions. In addition to pointing out the numerous benefits, the challenges of implementing mass spectrometry in the clinical laboratory are also covered.

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Section: Advantages Of Msmentioning

confidence: 97%

Effective Use of Mass Spectrometry in the Clinical Laboratory

2016

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“…Furthermore, several reports have proposed estimation of whole-blood tacrolimus concentration by evaluating tacrolimus concentration in washed erythrocytes and hematocrit. 7,9 However, calculating the falsely detected tacrolimus concentration is difficult, unless an apparent abnormal range is observed. The approaches mentioned above are available only to check whether tacrolimus concentrations are false-positive or not.…”

Section: Discussionmentioning

confidence: 99%

“…However, several cases of false abnormally elevated tacrolimus/cyclosporine concentrations measured by the ACMIA in patients who had undergone kidney, liver, or heart transplant have been reported. [7][8][9][10] A literature review of falsely detected tacrolimus/cyclosporine concentrations as measured by the ACMIA is shown in Table 2. Furthermore, Moscato and associates have reported a systematic analysis of the extent of false-positive results of tacrolimus concentration obtained by the ACMIA that was observed in 10 of 1058 patients (approximately 1%), compared with that obtained by the liquid chromatography-tandem mass spectroscopy reference method.…”

Section: Discussionmentioning

confidence: 99%

“…Because of these events, we suspected a false detection of tacrolimus/cyclosporine concentrations by the ACMIA as shown in previous reports. 7 To check false detection of tacrolimus concentration, we measured tacrolimus concentration in plasma and washed erythrocytes. The value of tacrolimus concentration in plasma and washed erythrocytes was 2.3 ng/mL and zero (Table 1), although approximately 80% of tacrolimus in blood is distributed in erythrocytes.…”

Section: Casementioning

confidence: 99%

“…However, in the last decade, some cases have been described in which the blood tacrolimus concentrations as measured by the ACMIA revealed falsely elevated drug concentrations in kidney, liver, and heart transplant recipients. [7][8][9][10] Fortunately, the values described were remarkably toxic concentrations; therefore, health care professionals immediately noticed the abnormal values were incorrect because of the inconsistency of clinical symptoms. Unlike previous cases, we recently saw cases that showed falsely detected tacrolimus concentrations (although they were within the therapeutic range).…”

Section: Introductionmentioning

confidence: 99%

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Taguchi

Ohmura²,

Ohya³

et al. 2014

Exp Clin Transplant

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Safe use of tacrolimus relies on regular whole-blood drug monitoring. Of the methods used to assess whole-blood tacrolimus concentration, antibodyconjugated magnetic immunoassay is mostly used for therapeutic drug monitoring because it requires only a minimal sample preparation and no pretreatment procedure. However, several cases recently have been reported in which abnormally false elevated tacrolimus concentrations were measured by antibody-conjugated magnetic immunoassay (>15 ng/mL), despite the absence of clinical symptoms.We present 2 cases of falsely detected tacrolimus concentrations that did not show abnormally high values within the therapeutic range. Whole-blood tacrolimus concentrations obtained by antibodyconjugated magnetic immunoassay showed wellcontrolled concentrations (approximately 2-8 ng/mL), whereas those obtained by another immunoassay and in washed erythrocytes were below the assay range (< 1.2 ng/mL). Thus, antibody-conjugated magnetic immunoassay can elicit falsely positive results of tacrolimus concentrations, even though they are within the therapeutic range.

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Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

2015

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Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic hematopoietic cell transplant (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared to solid organ transplant, alloHCT is unique because of the potential for bi-directional reactions (i.e., host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATG) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants’ pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source, and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressives deserves to be explored in depth. The development of sophisticated systems pharmacology models and improved TCI tools are needed to accurately evaluate patients’ exposure to drugs in general and to immunosuppressants in particular. Sequential studies, first without and then with TCI, should be conducted to validate the clinical benefit of TCI in homogenous populations; randomized trials are not feasible due to higher priority research questions in alloHCT. In part I of this article, we review the alloHCT process to facilitate optimal design of pharmacokinetic and pharmacodynamics studies. We also review the pharmacokinetics and TCI of calcineurin inhibitors and methotrexate.

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Falsely Increased Blood Tacrolimus Concentrations Using the ACMIA Assay Due to Circulating Endogenous Antibodies in a Liver Transplant Recipient: A Tentative Approach to Obtaining Reliable Results

Cited by 45 publications

References 14 publications

Effective Use of Mass Spectrometry in the Clinical Laboratory

Effective Use of Mass Spectrometry in the Clinical Laboratory

Untitled

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

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