title: Development of an UPLC-MS/MS method for quantification of Avitinib (AC0010) and its five metabolites in human cerebrospinal fluid: Application to a study of the blood-brain barrier penetration rate of non-small cell lung cancer patients.
abstract: Avitinib (AC0010) is a mutant-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), designed to be a targeted therapeutic agent for non-small cell lung cancer (NSCLC) patients harboring EGFR active and T790M resistant mutations. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of Avitinib and its five metabolites (M1, M2, M4, M7, MII-6) in human cerebrospinal fluid (CSF). The samples were purified by protein precipitation and separated on a BEH C18column (2.1×50mm, 1.7μm). Electrospray ionization (ESI) in positive ion mode and multiple reaction monitoring (MRM) were used to monitor the ion transitions at m/z 488/257, 474/403, 504/487, 434/377, 490/405, 476/391. The results indicated that the method had excellent sensitivity and specificity. The linear range covered from 0.05 to 50ng/mL for Avitinib, M1, M4, M7, and MII-6, and from 0.01 to 10ng/mL for M2. Intra-day and inter-day precisions (in terms of% RSD) were all <15% and the accuracies (in terms of% RE) were within the range of ±15%. The lower limit of quantification (LLOQ), matrix effect, extraction recovery, stability and dilution integrity were also validated and satisfied with the criteria of validation. Finally, the method was successfully applied to a blood-brain barrier (BBB) penetration rate research of NSCLC patients after an oral administration of Avitinib.
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China.
authors.forename: Weicong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China.
authors.forename: Hanping
authors.initials: H
authors.lastname: Wang
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China. Electronic address: pei.hu.pumc@gmail.com.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors
keywords: AC0010; Avitinib; Cerebrospinal fluid; EGFR-TKI; NSCLC; UPLC–MS/MS