Development and Validation of UPLC-MS/MS Method for Determination of Enasidenib in Rat Plasma and Its Pharmacokinetic Application

Li, Shuang-long; Zhu, Yongliang; Zhang, Yi; Liu, Shuhan; Wang, Xiang-die; Qiu, Xiangjun

doi:10.1155/2020/5084127

“…has the advantages of high sensitivity, strong specificity, short analysis time, and good reproducibility. erefore, it is often used in the detection of biological samples and the study of pharmacokinetics [18,19].…”

Section: Methods Validation and Improvement Uplc-ms/msmentioning

confidence: 99%

Validated UPLC-MS/MS Method for Determination of Futibatinib and Its Pharmacokinetics in Beagle Dogs

Li

¹

,

Ding

²

,

Wang

³

et al. 2022

Journal of Chemistry

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Futibatinib, a highly selective, irreversible potent fibroblast growth factor receptor (FGFR) inhibitor, has been proved to be effective in clinical trials of intrahepatic cholangiocarcinoma (ICCA) patients. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to determine the concentration of futibatinib in beagle dog plasma was developed and validated for the study of pharmacokinetics. After the plasma protein was removed by acetonitrile precipitation, futibatinib was detected and derazantinib was used as the internal standard (IS). Futibatinib and IS were separated in an UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with acetonitrile and 0.1% formic acid as the mobile phase, and the flow rate was 0.3 mL/min. Under the positive ion condition of an electrospray spray ion (ESI+) source, multireaction detection was used, and the ion pairs for futibatinib and IS were m/z 418.99 ⟶ 295.97 and 468.96 ⟶ 382.00, respectively. Futibatinib had a good linear relationship in the linear range of 0.5∼100 ng/mL; the lower limit of quantification (LLOQ) was 0.5 ng/mL. The RSDs of the intraday and interday precision were all less than 10.70%, and the RE value of accuracy was between −3.87% and 3.28%. The extraction recovery of futibatinib was more than 80%, and the matrix effect was around 100%, and futibatinib was found to be stable under four experimental conditions. The new optimized and validated UPLC-MS/MS method was an effective tool to determine the concentration of futibatinib in plasma and has been successfully applied to the pharmacokinetics of futibatinib in beagle dogs. This method would also be used to study drug-drug interaction (DDI).

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“…[7][8][9] Few bioanalytical approaches have been reported for the determination of drugs in plasma and blood samples, according to a literature search. [10][11][12][13] Currently no literature is available on stress degradation studies and SIAM for EDB.…”

Section: Introductionmentioning

confidence: 99%

“…Pharmaceutical stress testing has been widely employed in formulation development to determine degradation products (DP) and associated reaction routes, predict drug stability issues, and develop stability‐indicating analytical procedures (stability‐indicating assay method [SIAM]) 7–9 . Few bioanalytical approaches have been reported for the determination of drugs in plasma and blood samples, according to a literature search 10–13 . Currently no literature is available on stress degradation studies and SIAM for EDB.…”

Section: Introductionmentioning

confidence: 99%

LC/Q‐TOF‐MS‐based structural characterization of enasidenib degradation products and establishment of a stability‐indicating assay method: Insights into chemical stability

Chakkar,

Chaturvedi,

Rajput

et al. 2024

Rapid Comm Mass Spectrometry

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RationaleEnasidenib (EDB) is an orally active selective mutant isocitrate dehydrogenase‐2 enzyme inhibitor approved by the U.S. Food and Drug Administration to treat acute myeloid leukemia. It lacks a reported forced degradation study and a stability‐indicating assay method (SIAM). This study addresses this gap by establishing a degradation profile in accordance with the International Council for Harmonisation Q1A and Q1B (R2) guidelines and developing a validated SIAM for EDB.MethodsEDB was exposed to forced degradation under various conditions (hydrolytic, photolytic, oxidative, and thermal stress). Degradation samples were analyzed using high‐performance liquid chromatography on an Agilent ZORBAX Eclipse Plus C18 column with a mobile phase consisting of 0.1% formic acid in Milli‐Q water and acetonitrile at a flow rate of 1 mL/min and detection at 270 nm. Liquid chromatography‐quadrupole time‐of‐flight‐high‐resolution mass spectrometry (LC/Q‐TOF HRMS) was used for the identification and characterization of degradation products. Nitrosamine risk assessment was conducted using a modified nitrosation assay procedure (NAP) test due to the presence of a secondary amine group in the drug, which is liable to forming nitrosamine drug substance–related impurities (NDSRI).ResultsThe drug exhibited significant degradation under acidic, basic, photolytic, and oxidative conditions in the solution state. A total of nine degradation products (DP) were formed (DP‐I, DP‐III, and DP‐IV: acidic conditions; DP‐I and DP‐III: basic conditions; DP‐II, DP‐V, DP‐VI, and DP‐VII: oxidative stress; and DP‐VII, DP‐VIII, and DP‐IX: photolytic conditions), which were separated and identified using reversed‐phase high‐performance liquid chromatography and characterized using liquid chromatography–tandem mass spectrometry. The mechanism behind the formation of EDB degradation products has been discussed, and this study was the first to develop a degradation pathway for EDB. In addition, the possibilities of NDSRI formation for EDB were studied using a modified NAP test, which can contribute to the risk assessment of the drug.ConclusionsForced degradation studies were conducted by establishing a SIAM for EDB. All the degradation products were characterized by mass spectral data obtained using LC/Q‐TOF‐HRMS.

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“…Therefore, according to the previous research on the methodology of detecting enasidenib by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) [ 16 ], in this study, a sensitive, rapid, and simple method for determination of enasidenib in rat plasma by UPLC-MS/MS was developed and performed using ivosidenib as the internal standard (IS, Figure 1(b) ), and the effect of XAPI on the changes of pharmacokinetics of enasidenib in rats was observed.…”

Section: Introductionmentioning

confidence: 99%

UPLC‐MS/MS for the Herb‐Drug Interactions of Xiao‐Ai‐Ping Injection on Enasidenib in Rats Based on Pharmacokinetics

Wang

¹

,

Qiu

²

,

Tang

³

et al. 2021

BioMed Research International

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Objective. To develop and validate a sensitive and rapid ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of enasidenib in rat plasma and to investigate the effect of Xiao-ai-ping injection (XAPI) on the pharmacokinetics of enasidenib in rats. Methods. The rat plasma was precipitated with acetonitrile, enasidenib and internal standard (IS) were separated on an Acquity UPLC BEH C18 column, and acetonitrile and 0.1% formic acid were used as the mobile phase in gradient mode. Enasidenib and IS were monitored and detected by multiple reaction monitoring (MRM) using tandem mass spectrometry in positive ion mode. 12 Sprague-Dawley (SD) rats were randomly divided into control group (group A) and experimental group (group B), 6 rats in each group. Group B was intramuscularly injected with XAPI (0.3 mL/kg) every morning, 7 days in a row. Group A was intramuscularly injected with normal saline, 7 days in a row. On the seventh day, enasidenib (10 mg/kg) was given to both groups 30 min after injection of normal saline (group A) or XAPI (group B), and the blood was collected at different time points such as 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 h. The concentration of enasidenib was detected by UPLC-MS/MS, and the main parameters of pharmacokinetic of enasidenib were calculated using the DAS 2.0 software. Results. Under the current experimental conditions, this UPLC method showed good linearity in the detection of enasidenib. Interday and intraday precision did not exceed 10%, the range of accuracy values were from -1.43% to 2.76%. The results of matrix effect, extraction recovery, and stability met the requirements of FDA approval guidelines of bioanalytical method validation. The C max of enasidenib in the group A and the group B was ( 458.87 ± 136.02 ) ng/mL and ( 661.47 ± 107.32 ) ng/mL, t 1 / 2 was ( 7.74 ± 0.91 ) h and ( 8.64 ± 0.42 ) h, AU C 0 − t was ( 4067.24 ± 1214.36 ) ng·h/mL and ( 5645.40 ± 1046.30 ) ng·h/mL, AU C 0 − ∞ was ( 4125.79 ± 1235.91 ) ng·h/mL and ( 5759.61 ± 1078.59 ) ng·h/mL, respectively. The C max of enasidenib in group B was 44.15% higher than that in group A, and the AU C 0 − t and AU C 0 − ∞ of enasidenib in group B were 38.80% and 39.60% higher than that in group A, respectively, and the t 1 / 2 was prolonged from 7.74 h to 8.64 h. Conclusion. An UPLC-MS/MS method for the determination of enasidenib in rat plasma was established. XAPI can inhibit the metabolism of enasidenib and increase the concentration of enasidenib in rats. It is suggested that when XAPI was combined with enasidenib, the herb-drug interaction and adverse reactions should be paid attention to, and the dosage should be adjusted if necessary.

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Development and Validation of UPLC-MS/MS Method for Determination of Enasidenib in Rat Plasma and Its Pharmacokinetic Application

Cited by 3 publications

References 16 publications

Validated UPLC-MS/MS Method for Determination of Futibatinib and Its Pharmacokinetics in Beagle Dogs

Validated UPLC-MS/MS Method for Determination of Futibatinib and Its Pharmacokinetics in Beagle Dogs

LC/Q‐TOF‐MS‐based structural characterization of enasidenib degradation products and establishment of a stability‐indicating assay method: Insights into chemical stability

UPLC‐MS/MS for the Herb‐Drug Interactions of Xiao‐Ai‐Ping Injection on Enasidenib in Rats Based on Pharmacokinetics

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