Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance

Choong, Eva; Uppugunduri, Chakradhara Rao S.; Denis, Maxime; Melanie, Kuntzinger; Doffey-Lazeyras, Fabienne; Rodolfo, Lo Piccolo; Chalandon, Yves; Peters, Christina; Daali, Youssef; Ansari, Marc

doi:10.1097/ftd.0000000000000468

Cited by 24 publications

(6 citation statements)

References 47 publications

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“…In order to make Bu TDM less invasive, faster and easier, we developed and validated an HPLC-MS/MS analytical method to replace or support our old, accurate and robust HPLC-UV method, that successfully passed all the phases of an international, multicenter Bu cross-validation [14] and was regarded as our gold standard analytical method.…”

Section: Discussionmentioning

confidence: 99%

“…In order to make Bu TDM less invasive, faster and easier, we developed and validated a high-performance liquid chromatography (HPLC) MS/MS analytical method to replace or support our old, accurate, robust reference assay, that successfully passed all the phases of an international multicenter Bu cross-validation [14], and is regarded as our gold standard analytical method. To investigate the agreement in estimated AUC values, Lin's concordance correlation coefficient (CCC) was calculated and a Bland-Altman plot was created.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Two Analytical Methods for Busulfan Therapeutic Drug Monitoring

Gregori

Tinelli

Manzoni

et al. 2020

Eur J Drug Metab Pharmacokinet

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Background and Objectives Busulfan (Bu) is an old drug, but is still well recommended as an alkylating agent during conditioning therapy, before hematopoietic stem cell transplantation. Although its dose administration is standardized and based on patient weight, therapeutic drug monitoring is required in order to maintain its exposure [as area under the concentrationtime curve (AUC) from 0 to infinity AUC 0-∞ ] within a narrow therapeutic range and, if necessary, to adjust the dose with as short a lead time as possible. The aim of the study is to evaluate the agreement (as calculated AUC) between a gold standard analytical method and a new one that is faster and easier. Methods We analyzed 221 plasma samples from 37 children (0.25-16 years; 4-62.5 kg) and 11 adults (21-59 years; 45-80 kg), corresponding to 52 AUC values (ng h/mL). The drug exposure was calculated, simultaneously, by two validated analytical methods. The reference method was a high-performance liquid chromatography (HPLC) assay combined with an ultraviolet detector (UV). The test method had a triple quadrupole mass spectrometer (MS) as detector; the clean-up procedures of the samples were different and faster. Results The agreement between the two methods (reference and test) was evaluated in terms of Bu exposure differences based on Lin's concordance correlation coefficient (CCC) and represented by the Bland-Altman plot. The CCC between the AUC of the two methods was excellent (0.868; 95% CI: 0.802-0.935). The precision of the measures (expressed by Pearson's italic "r") was 0.872, and the accuracy (accounted by the bias correction factor) was 0.996. Conclusions We can conclude that the HPLC-MS/MS assay represents a very good alternative to the reference.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of Two Analytical Methods for Busulfan Therapeutic Drug Monitoring

Gregori

Tinelli

Manzoni

et al. 2020

Eur J Drug Metab Pharmacokinet

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“…Human blood plasma or serum are the most commonly studied bodily fluids for disease diagnosis, biomarker discovery and therapeutic drug monitoring [51][52][53][54][55][56][57]. While plasma and serum are both cell-free fluids obtained from blood samples by centrifugation, they differ on the basis of whether clotting has been allowed or not.…”

Section: Measurement Of Plasma Vs Serummentioning

confidence: 99%

Potential of Raman spectroscopy for the analysis of plasma/serum in the liquid state: recent advances

2020

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There is compelling evidence in the literature to support the application of Raman spectroscopy for analysis of bodily fluids in their native liquid state. Naturally, the strategies described in the literature for Raman spectroscopic analysis of liquid samples have advantages and disadvantages. Herein, recent advances in the analysis of plasma/serum in the liquid state are reviewed. The potential advantages of Raman analysis in the liquid form over the commonly employed infrared absorption analysis in the dried droplet form are initially highlighted.Improvements in measurement protocols based on inverted microscopic geometries, clinically adaptable substrates, data preprocessing and analysis, and applications for routine monitoring of patient health as well as therapeutic administration are reviewed. These advances suggest that clinical translation of Raman spectroscopy for rapid biochemical analysis can be a reality.In the future, this method will prove to be highly beneficial to clinicians for rapid screening and monitoring of analytes and drugs in the biological fluids, and to the patients themselves, enabling early treatment, before the disease becomes symptomatic, allowing early recovery.

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“…1 A critical step before HSCT is myeloablation, and busulfan (BU; 1,4butanediol-dimethanesulfonate) is currently one of the most commonly used myeloablative agents. 2,3 BU is a chemotherapy drug with high cellular toxicity, narrow therapeutic index, and high intraindividual pharmacokinetic variability. 4,5 The relationship between exposure to BU and therapeutic outcomes, in terms of toxicity and efficacy, has already been established.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 The relationship between exposure to BU and therapeutic outcomes, in terms of toxicity and efficacy, has already been established. 2,[5][6][7] Therapeutic drug monitoring (TDM) of BU during high-dose conditioning is usually performed using plasma concentrations, based on the area under the curve (AUC) calculations. 8 Different AUC targets are applied, depending on dosing frequency.…”

Section: Introductionmentioning

confidence: 99%

Dried Plasma Spots and Oral Fluid as Alternative Matrices for Therapeutic Drug Monitoring of Busulfan: Analytical Method Development and Clinical Evaluation

Granzotto

Silva

Lizot

et al. 2021

Therapeutic Drug Monitoring

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Background: Busulfan (BU) is an alkylating agent with a narrow therapeutic index and high intraindividual pharmacokinetic variability used in conditioning therapy for hematopoietic stem cell transplantation. Monitoring BU exposure during high-dose conditioning regimens is recommended and positively impacts outcomes. We aimed to develop, validate, and apply a ultra-high-performance liquid chromatography-mass spectrometry (MS)/MS assay to measure BU concentrations in oral fluid and dried plasma spots (DPS) as alternative matrices to plasma. Methods:We prepared plasma and oral fluid samples by protein precipitation and DPS after liquid extraction. We analyzed extracts using an LC-MS/MS system with an Acquity HSS T3 column in the positive electrospray ionization mode. The method was validated and applied to 79 paired plasma and oral fluid samples from 7 patients on BU conditioning treatment. DPS were prepared by pipetting plasma onto Whatman 903 paper. The correlation between BU in plasma, oral fluid, and DPS samples was evaluated.Results: Run time was 4.0 minutes. The assay was linear at 50-5000 ng mL 21 (r . 0.99), precise (1.9%-5.3% oral fluid and 1.8%-5.9% DPS), and accurate (98.1%-108.9% oral fluid and 93%-103.1% DPS). BU was stable in DPS at 238C for 24 hours. BU levels in oral fluid (r = 0.927) and DPS (r = 0.982) were significantly correlated with plasma. Despite the good correlation, we found a wide variation between oral fluid and plasma levels. The area under curves (AUCs) calculated with oral fluid concentrations were 79.1%-167.1% of plasma AUCs. Bland-Altman plots found a better agreement for DPS, with AUCs estimated from corrected DPS levels at 83.1%-114.1% of plasma values. Conclusions:We developed and validated a simple and fast ultrahigh-performance liquid chromatography-MS/MS assay to measure BU in oral fluid and DPS. The results do not support the use of oral fluid as a matrix for routine therapeutic drug monitoring of BU. The AUC estimated from BU measurements in DPS was comparable to that in plasma, supporting the use of DPS in BU therapeutic drug monitoring as an alternative matrix, with adequate short-term stability and logistic advantages.

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Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance

Abstract: We conclude that TDM is an effective method of achieving targeted Bu levels in children. QC programs are crucial to monitoring and maintaining the quality of an analytical method.

Cited by 24 publications

References 47 publications

Comparison of Two Analytical Methods for Busulfan Therapeutic Drug Monitoring

Comparison of Two Analytical Methods for Busulfan Therapeutic Drug Monitoring

Potential of Raman spectroscopy for the analysis of plasma/serum in the liquid state: recent advances

Dried Plasma Spots and Oral Fluid as Alternative Matrices for Therapeutic Drug Monitoring of Busulfan: Analytical Method Development and Clinical Evaluation

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