Development and application of an LC-MS/MS method for pharmacokinetic study of ruxolitinib in children with hemophagocytic lymphohistiocytosis
Ruxolitinib (RUX), a small molecule inhibitor of JAK1/JAK2, has been identified as the possible novel targeted agent for the treatment of hemophagocytic lymphohistiocytosis (HLH). However, due to the lack of randomized clinical trials (RCTs), it is extremely difficult to determine the effective therapeutic dose for RUX in HLH patients, especially in pediatric patients. At the same time, the clinical response of pediatric patients to RUX varies greatly among individuals according to several case reports. Therefore, it is imperative to investigate the pharmacokinetic and pharmacodynamic characteristics of RUX in HLH children, and this must be based on a satisfactory method to determine the concentration of RUX. Owing to several limits of published analytical methods, herein, we describe a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method for monitoring RUX in children's plasma samples. The protein precipitation method using methanol was used for sample cleanup. The analytes were separated by gradient elution in which 2.0 mM ammonium acetate in distilled water and acetonitrile were used as mobile phases. In the positive electrospray ionization (ESI+) mode, the m/z 307.1 → 186.0 and 316.1 → 185.9 ion pair transitions of RUX and RUX-d9 were used for the qualitative and quantitative analysis, respectively. The calibration curves of RUX were linear in the concentration range from 0.5 to 400 ng mL-1. The intra- and inter-batch precision, accuracy, recovery, dilution completeness, and stability of this method were all within acceptable standards, and no matrix effects or residues were found. This method was successfully applied to the clinical pharmacokinetic study of RUX in 32 children with HLH. The pharmacokinetic parameters of HLH children after a single dose of RUX and the steady state plasma concentration after multiple administrations were proposed through this method. Most importantly, it was found that the age and serum creatinine (SCr) of children with HLH had a significant and complex impact on the in vivo process of RUX after the single as well as multiple administrations of RUX.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Analytical methods : advancing methods and applications - 14(2022), 23 vom: 16. Juni, Seite 2293-2303 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Zhuo [VerfasserIn] |
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| Links: |
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| Themen: |
82S8X8XX8H |
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| Anmerkungen: |
Date Completed 20.06.2022 Date Revised 19.07.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1039/d2ay00533f |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM341578029 |
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| 100 | 1 | |a Li, Zhuo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Development and application of an LC-MS/MS method for pharmacokinetic study of ruxolitinib in children with hemophagocytic lymphohistiocytosis |
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| 520 | |a Ruxolitinib (RUX), a small molecule inhibitor of JAK1/JAK2, has been identified as the possible novel targeted agent for the treatment of hemophagocytic lymphohistiocytosis (HLH). However, due to the lack of randomized clinical trials (RCTs), it is extremely difficult to determine the effective therapeutic dose for RUX in HLH patients, especially in pediatric patients. At the same time, the clinical response of pediatric patients to RUX varies greatly among individuals according to several case reports. Therefore, it is imperative to investigate the pharmacokinetic and pharmacodynamic characteristics of RUX in HLH children, and this must be based on a satisfactory method to determine the concentration of RUX. Owing to several limits of published analytical methods, herein, we describe a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method for monitoring RUX in children's plasma samples. The protein precipitation method using methanol was used for sample cleanup. The analytes were separated by gradient elution in which 2.0 mM ammonium acetate in distilled water and acetonitrile were used as mobile phases. In the positive electrospray ionization (ESI+) mode, the m/z 307.1 → 186.0 and 316.1 → 185.9 ion pair transitions of RUX and RUX-d9 were used for the qualitative and quantitative analysis, respectively. The calibration curves of RUX were linear in the concentration range from 0.5 to 400 ng mL-1. The intra- and inter-batch precision, accuracy, recovery, dilution completeness, and stability of this method were all within acceptable standards, and no matrix effects or residues were found. This method was successfully applied to the clinical pharmacokinetic study of RUX in 32 children with HLH. The pharmacokinetic parameters of HLH children after a single dose of RUX and the steady state plasma concentration after multiple administrations were proposed through this method. Most importantly, it was found that the age and serum creatinine (SCr) of children with HLH had a significant and complex impact on the in vivo process of RUX after the single as well as multiple administrations of RUX | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
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| 700 | 1 | |a Sun, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Hong-Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yun-Ze |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Chang-Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Li-Bo |e verfasserin |4 aut | |
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