Development and validation of an LC-MS/MS method for monitoring larotrectinib, a tropomyosin-related kinase inhibitor, in mouse and human plasma and application to pharmacokinetic studies

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Title
Development and validation of an LC-MS/MS method for monitoring larotrectinib, a tropomyosin-related kinase inhibitor, in mouse and human plasma and application to pharmacokinetic studies
Author(s)
Y J Chae; Yoo-Kyung Song; Song Hee Chae; Min Ju KimJong Soon Kang; J Y Lee; T S Koo; Kyeong-Ryoon Lee
Bibliographic Citation
Journal of Analytical Science and Technology, vol. 11, pp. 20-20
Publication Year
2020
Abstract
Larotrectinib is an orally administered drug and the first and only selective pan-tropomyosin receptor kinase (TRK) inhibitor in clinical development to treat cancer patients harboring a neurotrophic receptor tyrosine kinase gene fusion. In this study, an analytical method to quantify the TRK inhibitor in mouse and human plasma was developed and validated using LC-MS/MS following protein precipitation with acetonitrile. Larotrectinib and an internal standard (carbamazepine) were separated from endogenous substances using an Xterra C18 column with acetonitrile containing 0.1% formic acid as the mobile phase. The ions m/z 429.8 → 342.8 for larotrectinib and m/z 237.0 → 194.0 for carbamazepine detected in multiple reaction monitoring mode were used for the quantitation. The detector response of larotrectinib was linear within the concentration range 5?10,000 ng/mL with a correlation coefficient (r2) of not less than 0.999. The intra- and inter-day precision and accuracy were less than 10.48% and within ? 8.99%, respectively, in mouse and human plasma. Larotrectinib was stable under various storage and handling conditions, and no significant matrix effect was observed in both mouse and human plasma. Finally, the assay was successfully applied to the pharmacokinetic study of larotrectinib after its intravenous and oral administration to mice.
Keyword
LarotrectinibTRK inhibitorPharmacokineticsMass spectrometry
ISSN
2093-3134
Publisher
Springer
DOI
http://dx.doi.org/10.1186/s40543-020-00219-5
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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