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Development and validation of a sensitive LC-MS/MS assay for the simultaneous quantification of allitinib and its two metabolites in human plasma.
J Pharm Biomed Anal 2013; 86:49-55JP

Abstract

Allitinib, also known as AST1306, is a novel irreversible inhibitor of the epidermal growth factor receptors 1 and 2. Allitinib is currently used in clinical trial to treat solid tumors. A previous study showed that allitinib is extensively metabolized in humans. Amide hydrolysis metabolite (M6) and 29,30-dihydrodiol allitinib (M10) are the major metabolites in circulation. To study the pharmacokinetics of allitinib and its two major metabolites in cancer patients, a rapid, sensitive and reliable LC-MS/MS method was developed and validated for the simultaneous determination of allitinib, M6 and M10 in human plasma. After simple protein precipitation, the analytes and the combined internal standards (lapatinib and NB-2, an analog of allitinib) were separated on a Zorbax Eclipase XDB C18 column (50 mm × 4.6 mm, 1.8 μm, Agilent) using a mobile phase of 5 mM ammonium acetate with 0.1% formic acid (phase A) and 50% (v/v) methanol in acetonitrile (phase B) with gradient elution. Mass spectrometric detection was conducted by atmospheric-pressure chemical ionization in positive ion multiple reaction monitoring modes using AB Sciex Triple Quad 6500 system. Linear calibration curves were obtained for the following concentration range: 0.300-200 ng/ml for allitinib; 0.030-20.0 ng/ml for M6; and 0.075-50.0 ng/ml for M10. Intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all of the concentrations. The method was successfully applied to a preliminary clinical pharmacokinetic study following oral administration of allitinib tosylate tablets in cancer patients.

Authors+Show Affiliations

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Validation Studies

Language

eng

PubMed ID

23973791

Citation

Lin, Lishan, et al. "Development and Validation of a Sensitive LC-MS/MS Assay for the Simultaneous Quantification of Allitinib and Its Two Metabolites in Human Plasma." Journal of Pharmaceutical and Biomedical Analysis, vol. 86, 2013, pp. 49-55.
Lin L, Gao Z, Chen X, et al. Development and validation of a sensitive LC-MS/MS assay for the simultaneous quantification of allitinib and its two metabolites in human plasma. J Pharm Biomed Anal. 2013;86:49-55.
Lin, L., Gao, Z., Chen, X., & Zhong, D. (2013). Development and validation of a sensitive LC-MS/MS assay for the simultaneous quantification of allitinib and its two metabolites in human plasma. Journal of Pharmaceutical and Biomedical Analysis, 86, pp. 49-55. doi:10.1016/j.jpba.2013.07.003.
Lin L, et al. Development and Validation of a Sensitive LC-MS/MS Assay for the Simultaneous Quantification of Allitinib and Its Two Metabolites in Human Plasma. J Pharm Biomed Anal. 2013;86:49-55. PubMed PMID: 23973791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development and validation of a sensitive LC-MS/MS assay for the simultaneous quantification of allitinib and its two metabolites in human plasma. AU - Lin,Lishan, AU - Gao,Zhiwei, AU - Chen,Xiaoyan, AU - Zhong,Dafang, Y1 - 2013/07/19/ PY - 2013/06/14/received PY - 2013/06/25/revised PY - 2013/07/03/accepted PY - 2013/8/27/entrez PY - 2013/8/27/pubmed PY - 2014/5/27/medline KW - APCI KW - Allitinib KW - ErbB KW - FDA KW - Food and Drug Administration KW - Human plasma KW - IS KW - LC–MS/MS KW - LLOQ KW - Liquid chromatography–tandem mass spectrometry KW - MRM KW - Metabolite KW - Pharmacokinetics KW - QC KW - RE KW - RSD KW - S/N KW - ULOQ KW - atmospheric-pressure chemical ionization KW - erythroblastic leukemia viral oncogene homolog KW - internal standard KW - liquid chromatography−tandem mass spectrometry KW - lower limit of quantification KW - multiple reaction monitoring KW - quality control KW - relative error KW - relative standard deviation KW - signal to noise KW - upper limit of quantification SP - 49 EP - 55 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 86 N2 - Allitinib, also known as AST1306, is a novel irreversible inhibitor of the epidermal growth factor receptors 1 and 2. Allitinib is currently used in clinical trial to treat solid tumors. A previous study showed that allitinib is extensively metabolized in humans. Amide hydrolysis metabolite (M6) and 29,30-dihydrodiol allitinib (M10) are the major metabolites in circulation. To study the pharmacokinetics of allitinib and its two major metabolites in cancer patients, a rapid, sensitive and reliable LC-MS/MS method was developed and validated for the simultaneous determination of allitinib, M6 and M10 in human plasma. After simple protein precipitation, the analytes and the combined internal standards (lapatinib and NB-2, an analog of allitinib) were separated on a Zorbax Eclipase XDB C18 column (50 mm × 4.6 mm, 1.8 μm, Agilent) using a mobile phase of 5 mM ammonium acetate with 0.1% formic acid (phase A) and 50% (v/v) methanol in acetonitrile (phase B) with gradient elution. Mass spectrometric detection was conducted by atmospheric-pressure chemical ionization in positive ion multiple reaction monitoring modes using AB Sciex Triple Quad 6500 system. Linear calibration curves were obtained for the following concentration range: 0.300-200 ng/ml for allitinib; 0.030-20.0 ng/ml for M6; and 0.075-50.0 ng/ml for M10. Intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all of the concentrations. The method was successfully applied to a preliminary clinical pharmacokinetic study following oral administration of allitinib tosylate tablets in cancer patients. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/23973791/Development_and_validation_of_a_sensitive_LC_MS/MS_assay_for_the_simultaneous_quantification_of_allitinib_and_its_two_metabolites_in_human_plasma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0731-7085(13)00299-9 DB - PRIME DP - Unbound Medicine ER -