Therapeutic drug monitoring of tacrolimus with the dried blood spot method

Hoogtanders, K.; Heijden, J. van der; Christiaans, Maarten H. L.; Edelbroek, Peter M.; Hooff, J. P. van; Stolk, L. M. L.

doi:10.1016/j.jpba.2006.11.023

Cited by 167 publications

(142 citation statements)

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“…In general, a minimum of 2-3 h drying in an open space at room temperature (15-22°C) is recommended (Edelbroek et al, 2009;Mei et al, 2001). However, the drying time depends on the type of paper/card and the blood volume applied (Hoogtanders et al, 2007;Koal et al, 2005;Spooner et al, 2009). The samples should not be heated, stacked or allowed to touch other surfaces, and should be kept away from direct sunlight or daylight if needed (Burhenne et al, 2008).…”

Section: Drying Storage and Transportationmentioning

confidence: 99%

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Dried blood spot sampling in combination with LC‐MS/MS for quantitative analysis of small molecules

Li¹,

Tse²

2009

Biomedical Chromatography

530

428

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The collection of whole blood samples on paper, known as dried blood spot (DBS), dates back to the early 1960s in newborn screening for inherited metabolic disorders. DBS off ers a number of advantages over conventional blood collection. As a less invasive sampling method, DBS off ers simpler sample collection and storage and easier transfer, with reduced infection risk of various pathogens, and requires a smaller blood volume. To date, DBS-LC-MS/MS has emerged as an important method for quantitative analysis of small molecules. Despite the increasing popularity of DBS-LC-MS/MS, the method has its limitations in assay sensitivity due to the small sample size. Sample quality is often a concern. Systematic assessment on the potential impact of various blood sample properties on accurate quantifi cation of analyte of interest is necessary. Whereas most analytes may be stable on DBS, unstable compounds present another challenge for DBS as enzyme inhibitors cannot be conveniently mixed during sample collection. Improvements on the chemistry of DBS card are desirable. In addition to capturing many representative DBS-LS-MS/MS applications, this review highlights some important aspects of developing and validating a rugged DBS-LC-MS/MS method for quantitative analysis of small molecules along with DBS sample collection, processing and storage.

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Section: Drying Storage and Transportationmentioning

confidence: 99%

“…The prepared standard and QC samples should mimic the study samples (Barfi eld et al, 2008;Edelbroek et al, 2009;Hoogtanders et al, 2007). Hemolyzed blood should be avoided.…”

Section: Blank Blood For Calibration Standards and Qcsmentioning

confidence: 99%

Dried blood spot sampling in combination with LC‐MS/MS for quantitative analysis of small molecules

Li¹,

Tse²

2009

Biomedical Chromatography

530

428

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“…In comparison with previously described LC-MS/MS assays to quantify tacrolimus in dried bloods spots [29][30][31][32][33][34]36,39,41,42 , the present assay matches or exceeds their performance in terms of lower limit of quantification, extraction recovery, accuracy and precision while avoiding potentially risky concepts such as one-step protein precipitation procedures and ultra-short chromatography times, which usually give acceptable results during the validation based on blood samples from healthy individuals. However, transplant patients are a highly complex group of patients who have diseases that affect the composition of blood and who take multiple medications.…”

Section: Discussionmentioning

confidence: 82%

“…After a simple finger stick the patient collects a blood drop on a special filter paper card and after the blood spot has dried, it can be mailed to a central laboratory for analysis of tacrolimus and any other immunosuppressant that the patient may currently be taking. This has become possible due to the development of highly sensitive and specific LC-MS/MS assays for the quantification of tacrolimus and other immunosuppressants in very small blood volumes such as dried blood spots (typically 20 µl of blood) 25,[29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] . Another advantage is that minimally invasive, low volume sample collection strategies such as dried blood spots greatly facilitate therapeutic drug monitoring and pharmacokinetic studies in small children 28 .…”

Section: Introductionmentioning

confidence: 99%

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

Shokati

Bodenberger

Gadpaille

et al. 2015

JoVE

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The calcineurin inhibitor tacrolimus is the cornerstone of most immunosuppressive treatment protocols after solid organ transplantation in the United States. Tacrolimus is a narrow therapeutic index drug and as such requires therapeutic drug monitoring and dose adjustment based on its whole blood trough concentrations. To facilitate home therapeutic drug and adherence monitoring, the collection of dried blood spots is an attractive concept. After a finger stick, the patient collects a blood drop on filter paper at home. After the blood is dried, it is mailed to the analytical laboratory where tacrolimus is quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) in combination with a simple manual protein precipitation step and online column extraction.For tacrolimus analysis, a 6-mm disc is punched from the saturated center of the blood spot. The blood spot is homogenized using a bullet blender and then proteins are precipitated with methanol/0.2 M ZnSO 4 containing the internal standard D 2, 13 C-tacrolimus. After vortexing and centrifugation, 100 µl of supernatant is injected into an online extraction column and washed with 5 ml/min of 0.1 formic acid/acetonitrile (7:3, v:v) for 1 min. Hereafter, the switching valve is activated and the analytes are back-flushed onto the analytical column (and separated using a 0.1% formic acid/acetonitrile gradient). Tacrolimus is quantified in the positive multi reaction mode (MRM) using a tandem mass spectrometer.The assay is linear from 1 to 50 ng/ml. Inter-assay variability (3.6%-6.1%) and accuracy (91.7%-101.6%) as assessed over 20 days meet acceptance criteria. Average extraction recovery is 95.5%. There are no relevant carry-over, matrix interferences and matrix effects. Tacrolimus is stable in dried blood spots at RT and at +4 °C for 1 week. Extracted samples in the autosampler are stable at +4 °C for at least 72 hr. Video LinkThe video component of this article can be found at

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“…[14][15][16][17][18][19] Esta técnica es muy poco invasiva ya que, sin necesidad de canalizar, se pueden obtener múltiples muestras sanguíneas de muy pequeño volumen, con la punción del talón o el dedo y se transfieren a papel filtro, donde se almacenan y se pueden analizar mucho tiempo después. Originalmente se planeó para detectar enfermedades metabólicas en el recién nacido.…”

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Farmacocinética comparada de metformina, en forma sólida y en formulación extemporánea líquida para pediatría, en voluntarios adultos sanos

et al. 2016

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191www.actapediatrica.org.mx artículo original Acta Pediatr Mex. 2016 jul;37(4):191-203. Farmacocinética comparada de metformina, en forma sólida y en formulación extemporánea líquida para pediatría, en voluntarios adultos sanos Resumen ANTECEDENTES: fraccionar o pulverizar tabletas de metformina para ajustar dosis pediátricas dificulta su administración, genera inestabilidad del fármaco (oxidación/fotosensibilidad) y relativiza su biodisponibilidad. Se propone como alternativa de ajuste de dosis y de uniformidad de contenido una formulación extemporánea líquida a partir de tabletas de marca comercial.OBJETIVO: determinar la biodisponibilidad de metformina en formulación líquida, en voluntarios adultos sanos, para demostrar que su comportamiento farmacocinético permanece inalterado. MATERIALES Y MÉTODOS:estudio clínico, aleatorio, cruzado y longitudinal, en adultos sanos voluntarios (n=12), 7 varones y 5 mujeres, de 24.3 ± 1.8 años, con índice de masa corporal = 24.9 ± 2.5 kg/m 2 . Se obtuvieron muestras sanguíneas en gotas, colectadas en tarjetas Whatman 903 ® , a las 0.25, 0.5, 1, 2, 4, 8 y 12 horas de ingerir 250 mg del fármaco. Se extrajo el fármaco a partir de 5 discos de papel filtro con sangre impregnada (16 μL), por precipitación directa, con acetonitrilo (ACN) y metanol. La detección fue en una columna AcQuity UPLC BEH HILIC (2.1 × 100mm, 1.7 μm) por espectrometría de masas en tándem. Fase móvil: acetato de amonio 5 mM y ACN (80:20; v/v), a 0.25 mL/ min isocráticamente. La farmacocinética se determinó mediante el programa Win Nonlin Pro 3.1 y las diferencias se evaluaron por ANOVA de una vía (p ≤ 0.05).RESULTADOS: el método fue exacto, preciso, selectivo y lineal entre 50 y 1000 ng/mL, coeficiente de determinación (r) de 0.9982. Las muestras extraídas y almacenadas a 4°C fueron estables por 17 horas y hasta 2 meses a -80°C. La metformina en tableta tuvo una C máx de 553.4 ng/mL y de 692.2 ng/mL con la formulación líquida. El T máx fue menor con la solución edulcorada (1.6 h) que con la tableta (1.8 h). La k e fue menor con la forma líquida (0.29 vs. 0.32 h -1 ), lo que sugiere que se eliminó más rápidamente. El AUC 0-12 fue igual en ambas formas (F=0.002, F crit =6.3).CONCLUSIONES: la formulación líquida de metformina es igualmente biodisponible que la forma farmacéutica original, con la ventaja de permitir dosis menores que la tableta, ajuste preciso de dosis y uniformidad de contenido. INTRODUCCIÓNActualmente el tratamiento farmacológico de la obesidad y la resistencia a insulina, como antesala de diabetes mellitus tipo II y síndrome metabólico en niños y adolescentes, es más frecuente debido al fracaso de la terapia con ejercicio y dieta, 1,2 a los malos hábitos alimenticios, Pharmacokinetics of metformin in split tablets and in a liquid extemporaneous formulation for paediatrics, in healthy adult volunteers.Abstract BACKGROUND: Homemade fractions of metformin tablets to adjust paediatric doses are difficult to administer, unstable and yields variable doses. In this work, a liquid extemporaneous ...

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Therapeutic drug monitoring of tacrolimus with the dried blood spot method

Cited by 167 publications

References 13 publications

Dried blood spot sampling in combination with LC‐MS/MS for quantitative analysis of small molecules

Dried blood spot sampling in combination with LC‐MS/MS for quantitative analysis of small molecules

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

Farmacocinética comparada de metformina, en forma sólida y en formulación extemporánea líquida para pediatría, en voluntarios adultos sanos

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