A New Method to Quantify Ifosfamide Blood Levels Using Dried Blood Spots and UPLC-MS/MS in Paediatric Patients with Embryonic Solid Tumours

Torres, L N Dicina; Rivera-Espinosa, Liliana; Chávez‐Pacheco, Juan Luis; Navas, Carlos F.; Demetrio, Joel A.; Alemón-Medina, Radamés; Trujillo, Francisca; Pérez, Martin; Zapata, Martha M.; Cárdenas, Rocío; Salinas, Citlaltepetl; Aquino, Arnoldo; Velázquez‐Cruz, Rafael; Castillejos, Manuel-de-Jesús

doi:10.1371/journal.pone.0143421

Cited by 15 publications

(10 citation statements)

References 16 publications

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“…In recent years, a method to quantify ifosfamide was developed in Mexico, using dried blood spots (DBS) on Güthrie cards (Whatman 903) for neonatal screening [ 13 ]. The DBS method has shown advantages over other methods, since it requires a single blood drop, a minimum amount of solvents and the quantification is faster, which significantly reduces its cost.…”

Section: Methodsmentioning

confidence: 99%

Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors

Espindola

López²,

Flores

et al. 2019

Arch Med Sci

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Introduction: The CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. genes contain several single nucleotide polymorphisms (SNPs) that confer different activity towards the enzyme. The aim of our study was to analyze gene frequencies of allelic variants and their association with ifosfamide blood levels and patient prognosis. Material and methods: 148 DNA samples from children were analyzed. Genotyping was performed by real-time PCR with TaqMan probes and ifosfamide levels were determined in dried blood drop by UPLCMS/MS. Results: Ifosfamide levels increased according to the genotype, and patients with the variant rs1799853 in CYP2C9 genotype CC had lower levels of ifosfamide (median = 1.8 μmol/l, Q 25 0.9-Q 75 4.6) compared with patients with genotype TT + CT (median = 2.8 μmol/l, Q 25 1.9-Q 75 5.1), p < 0.001. In the case of the rs2740574 variant in the CYP3A4 gene, patients with normal genotype (TT) presented median = 1.4 μmol/l, (Q 25 0.7-Q 75 2.7), while patients with the CC + TC genotype had higher levels of ifosfamide (median = 2.0 μmol/l, Q 25 1.0-Q 75 4.3), p = 0.024. In addition, patients with CC + CT genotype of this variant had a higher risk of non-response to treatment compared to patients with TT genotype (RR = 1.3, 95% CI: 1.07-1.59, p = 0.03). Conclusions: Polymorphisms in CYP2C9 and CYP3A4 genes are associated with high levels of ifosfamide. In addition, the polymorphism rs2740574 in CYP3A4 was associated with a worse therapeutic response.

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Section: Methodsmentioning

confidence: 99%

Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors

Espindola

López²,

Flores

et al. 2019

Arch Med Sci

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“…The optimization was performed by methanol and acetonitrile as a combination of extracting solution because they are polar so the analytes will be extracted into the solvent. Besides, that solvent also have been used on the extraction of ifosfamid and cyclophosphamide in DBS [16]. The optimum sample preparation were obtained by protein precipitation using 1000 µl methanolacetonitrile = 2:1 v/v.…”

Section: F Matrix Effectmentioning

confidence: 99%

“…time and 4 h after administration is an elimination time of both compounds [16,17]. Drug and their metabolites level in each patient can be different.…”

Section: F Matrix Effectmentioning

confidence: 99%

Method Development on Analysis Cyclophosphamide and 4-Hydroxycyclophophamide in Dried Blood Spot and Its Application in Breast Cancer Patients

et al. 2020

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Objective: To develop the method for the simultaneous analysis of cyclophosphamide and 4-hydroxycyclophosphamide (4-OHCP) in Dried Blood Spot (DBS) using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) and its application in breast cancer patients for therapeutic drug monitoring. Methods: Sample preparation used protein precipitation with methanol and acetonitrile (2:1 v/v). The separation was conducted using 1.7μm (2.1 x 100 mm) Waters AcquityTM UPLC C18 column; mobile phase consists of 0.01% formic acid and methanol (50:50 v/v) with isocratic elution, column temperature 30 °C, flow rate 0.3 ml/min and hexamethylphosphoramide (HMP) used as an internal standard. Analysis was performed by a triple quadrupole mass spectrometry with a positive ion mode of Electrospray Ionization. Cyclophosphamide was detected at m/z 260.968>139.978, 4-OHCP at m/z 338.011>224.979, and HMP at m/z 180.17>92.08. The method was applied to quantify cyclophosphamide and 4-OHCP in DBS of breast cancer patients. Blood samples were collected at 2 and 4 h after cyclophosphamide administration for therapeutic drug monitoring. Results: The method was linear in the range of 50–30.000 ng/ml for cyclophosphamide and 10–1000 ng/ml for 4-OHCP. Lower Limit of Quantification (LLOQ) concentration of cyclophosphamide was 50 ng/ml and 4-OHCP was 10 ng/ml. Accuracy and precision within-run and between-run met the requirements with % diff and CV, not exceeding ±15% and not more than ±20% for LLOQ concentration. The results from DBS samples of cancer patients showed that the level of cyclophosphamide was in the range of 6045.980 ng/ml to 37024.403 ng/ml and 4-OHCP was in the range 33.155 ng/ml to 246.362 ng/ml. Conclusion: The developed method met the requirements of all validation parameters under the Guideline on Bioanalytical Method Validation by the European Medicines Agency in 2011. Method can be applied on DBS of cancer patients and the results showed that cyclophosphamide and 4-OHCP was detected on 17 samples of breast cancer patients. This can be one of the parameters for therapeutic drug monitoring.

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“…Despite this, there is a growing interest in the application of DBS in oncology. DBS‐based methods have been described for the measurement of hormone therapy drugs, 42–44 antimetabolites, 45 alkylating agents, 46–49 taxanes, 50–53 vinca alkaloids 54 and topoisomerase inhibitors 55 . However, tyrosine kinase inhibitors are the class for which most DBS‐based studies have been published 56–63 .…”

Section: Sampling Strategiesmentioning

confidence: 99%

Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology

Menz

Stocker

Verougstraete

et al. 2020

Brit J Clinical Pharma

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There are few fields of medicine in which the individualisation of medicines is more important than in the area of oncology. Under‐dosing can have significant ramifications due to the potential for therapeutic failure and cancer progression; by contrast, over‐dosing may lead to severe treatment‐limiting side effects, such as agranulocytosis and neutropenia. Both circumstances lead to poor patient prognosis and contribute to the high mortality rates still seen in oncology. The concept of dose individualisation tailors dosing for each individual patient to ensure optimal drug exposure and best clinical outcomes. While the value of this strategy is well recognised, it has seen little translation to clinical application. However, it is important to recognise that the clinical setting of oncology is unlike that for which therapeutic drug monitoring (TDM) is currently the cornerstone of therapy (e.g. antimicrobials). Whilst there is much to learn from these established TDM settings, the challenges presented in the treatment of cancer must be considered to ensure the implementation of TDM in clinical practice. Recent advancements in a range of scientific disciplines have the capacity to address the current system limitations and significantly enhance the use of anticancer medicines to improve patient health. This review examines opportunities presented by these innovative scientific methodologies, specifically sampling strategies, bioanalytics and dosing decision support, to enable optimal practice and facilitate the clinical implementation of TDM in oncology.

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A New Method to Quantify Ifosfamide Blood Levels Using Dried Blood Spots and UPLC-MS/MS in Paediatric Patients with Embryonic Solid Tumours

Cited by 15 publications

References 16 publications

Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors

Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors

Method Development on Analysis Cyclophosphamide and 4-Hydroxycyclophophamide in Dried Blood Spot and Its Application in Breast Cancer Patients

Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology

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