Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method

Arellano, Cécile; Gandia, Peggy; Lafont, Thierry; Jongejan, Rutchanna M.S.; Chatelut, Étienne

doi:10.1016/j.jchromb.2012.09.007

Cited by 35 publications

(18 citation statements)

References 22 publications

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“…This sensitivity appears to be about 250 times greater than the previously reported LC-MS/MS. 12) In patients with CML, the steady-state trough plasma imatinib levels must exceed 1002 ng/mL to obtain clinical benefits, and these plasma concentrations of imatinib were associated with a clinical response.…”

Section: Resultsmentioning

confidence: 99%

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Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Saita

Shin

Fujito

2013

Biological & Pharmaceutical Bulletin

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Imatinib is an oral tyrosine kinase inhibitor used for first-line treatment of chronic myeloid leukemia. Therapeutic drug monitoring targeting trough plasma levels of about 1000 ng/mL may help to optimize imantinib's therapeutic effect. This paper reports a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for a pharmacokinetic evaluation of imatinib. Anti-imatinib antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin and succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. Enzyme labeling of imatinib with horseradish peroxidase was similarly performed using succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. A simple ELISA for imatinib was developed using the principle of direct competition between imatinib and the enzyme marker for anti-imatinib antibody which had been adsorbed by the plastic surface of a microtiter plate. Serum imatinib concentrations lower than 40 pg/mL were reproducibly measurable using the ELISA. This ELISA was specific to imatinib and showed very slight cross-reactivity (1.2%) with a major metabolite, N-desmethyl imatinib. Using this assay, drug levels were easily measured in the blood of mice after their oral administration of imatinib at a single dose of 50 mg/kg. The specificity and sensitivity of the ELISA for imatinib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of imatinib.

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Section: Resultsmentioning

confidence: 99%

“…Previous TDM and pharmacokinetic studies of imatinib were undertaken with high-performance liquid chromatography (HPLC) 10,11) and liquid chromatography with tandem mass spectrometry (LC-MS/MS), 12,13) which are specific, accurate, and reproducible methods. However, they require expensive instrumentation and a high degree of technical expertise.…”

mentioning

confidence: 99%

Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Saita

Shin

Fujito

2013

Biological & Pharmaceutical Bulletin

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“…[4][5][6] It performs its therapeutic activity on CML by competitive inhibition at the ATP-binding site. 4,7,8 This way, tyrosine kinase phosphorylation of proteins acting in Bcr-Abl signal transduction is inhibited. [7][8][9] In the clinical setting, Bcr-Abl positive cells are affected by the inhibition while normal cells are left unharmed.…”

Section: Imatinib and Norimatinib Plasma Levels Analyses Of Chronic Mmentioning

confidence: 99%

“…4,7,8 This way, tyrosine kinase phosphorylation of proteins acting in Bcr-Abl signal transduction is inhibited. [7][8][9] In the clinical setting, Bcr-Abl positive cells are affected by the inhibition while normal cells are left unharmed. 8 The primary aim of imatinib use in CML management is the achievement of a prolonged life span.…”

Section: Imatinib and Norimatinib Plasma Levels Analyses Of Chronic Mmentioning

confidence: 99%

“…[7][8][9] In the clinical setting, Bcr-Abl positive cells are affected by the inhibition while normal cells are left unharmed. 8 The primary aim of imatinib use in CML management is the achievement of a prolonged life span. 10 It is considered to be a clinically successful molecule due to its effectiveness and high tolerance profiles in CML patients.…”

Section: Imatinib and Norimatinib Plasma Levels Analyses Of Chronic Mmentioning

confidence: 99%

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Imatinib and Norimatinib Plasma Levels Analyses of Chronic Myeloid Leukemia Patients

Kilic¹,

Kayaaltı²,

Gündüz³

et al. 2016

Turkiye Klinikleri J Pharm Sci

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A AB BS S T TR RA AC CT T O Ob bj je ec ct ti iv ve e: : Imatinib is the first line treatment in chronic myeloid leukemia (CML). Imatinib metabolism depends primarily on the presence of cytochrome P450 enzymes, its active metabolite being norimatinib (N-desmethyl imatinib). Norimatinib accumulates in plasma 10-30%. The aim of this study was to analyze certain parameters which maintain the importance in clarifying the pharmacologic effects of imatinib. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : To investigate plasma concentrations, 41 CML patients on minimum 400 mg imatinib daily were included to the study. Pharmacokinetic analysis was performed by tandem mass spectrometry (LC-MS/MS). Mean plasma imatinib and norimatinib levels were statistically calculated as 4.038±1.290 ppm (min. 0.576 ppm, max. 6.795 ppm) and 1.150±0.733 ppm (min. 0.08 ppm, max. 3.835 ppm), respectively. R Re es su ul lt ts s: : Limit of detection (LOD) values for imatinib and norimatinib were 30 ppb and 25 ppb, whereas limit of quantification (LOQ) values were 99 ppb and 82.5 ppb, and recovery of imatinib and norimatinib were 98.45% and 92.47%, respectively. Average percentage of imatinib transformation to norimatinib was 22.16%. Variation of this percentage from one patient to another suggested the possibility of interindividual differences in drug response. C Co on nc cl lu us si io on n: : Individual results have shown that pharmacologic effects of imatinib may differentiate among patients. In this study, we standardized and justified the applicability of our analysis method. Patients' plasma drug levels can be measured using this method. Thus optimal treatment efficacy can be ensured.K Ke ey y W Wo or rd ds s: : İmatinib; pharmacokinetics; drug monitoring; leukemia, myeloid, chronic-phase; tandem mass spectrometry Ö ÖZ ZE ET T A Am ma aç ç: : İmatinib, kronik miyeloid lösemi tedavisinde ilk tercih edilen tedavi yöntemidir. İma-tinib metabolizması temelde sitokrom P450 enzimleri üzerinden, aktif metaboliti norimatinibe (Ndesmetil imatinibe) dönüşme şeklinde yürür. Norimatinib plazmada %10-30 aralığında birikme gösterir. Bu çalışmanın amacı, imatinibin farmakolojik etkilerini aydınlatmaya yardımcı olan parametrelerin analiz edilmesidir. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Plazma konsantrasyonlarının araştırılmasında, çalışmaya, günde en az 400 mg imatinib tedavisi gören 41 KML hastası dahil edildi. Plazma analizleri, tekrarlayan kütle spektrometrisi (LC-MS/MS) ile gerçekleştirildi. Ortalama plazma imatinib ve norimatinib düzeyleri istatistiksel yöntemlerle sırasıyla 4,038±1,290 ppm (min. 0,576 ppm, maks. 6,795 ppm) ve 1,150±0,733 ppm (min. 0,08 ppm, maks. 3,835 ppm) olarak hesaplandı. B Bu ul lg gu ul la ar r: : İmatinib ve norimatinib için saptama sınırı (LOD) değerleri sırasıyla 30 ppb ve 25 ppb, miktar tayini (LOQ) değerleri ise sırasıyla 99 ppb ve 82,5 ppb ve imatinib ile norimatinib için yüzde kazanım sırasıyla %98,45 ve %92,47 bulundu. İmatinibin norimatinibe ortalama dönüşüm yüzdesi %22,16 olarak he...

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Bioanalytical LC–MS/MS validation of therapeutic drug monitoring assays in oncology

Nuland

Rosing

Schellens

et al. 2019

Biomedical Chromatography

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Therapeutic drug monitoring (TDM) has shown to benefit patients treated with drugs of many drug classes, among which is oncology. With an increasing demand for drug monitoring, new assays have to be developed and validated. Guidelines for bioanalytical validation issued by the European Medicines Agency and US Food and Drug Administration are applicable for clinical trials and toxicokinetic studies and demand fully validated bioanalytical methods to yield reliable results. However, for TDM assays a limited validation approach is suggested based on the intended use of these methods. This review presents an overview of publications that describe method validation of assays specifically designed for TDM. In addition to evaluating current practice, we provide recommendations that could serve as a guide for future validations of TDM assays.

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Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC–MS/MS assay and ultrafiltration method

Cited by 35 publications

References 22 publications

Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Imatinib and Norimatinib Plasma Levels Analyses of Chronic Myeloid Leukemia Patients

Bioanalytical LC–MS/MS validation of therapeutic drug monitoring assays in oncology

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