Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry
Mohamed W Attwa, 1, 2 Adnan A Kadi, 1 Hany W Darwish 1, 3 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Students’ University Hospital, Mansoura University, Mansoura 35516, Egypt; 3Analytical Chemistry Department, Faculty...
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Dove Medical Press
2020-01-01
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| Series: | Drug Design, Development and Therapy |
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| Online Access: | https://www.dovepress.com/metabolic-stability-assessment-of-larotrectinib-using-liquid-chromatog-peer-reviewed-article-DDDT |
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| author | Attwa MW Kadi AA Darwish HW |
| author_facet | Attwa MW Kadi AA Darwish HW |
| author_sort | Attwa MW |
| collection | DOAJ |
| description | Mohamed W Attwa, 1, 2 Adnan A Kadi, 1 Hany W Darwish 1, 3 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Students’ University Hospital, Mansoura University, Mansoura 35516, Egypt; 3Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptCorrespondence: Hany W Darwish Tel +966 1146 77343Fax +966 1146 76 220Email hdarwish@ksu.edu.saIntroduction: Larotrectinib (VITRAKVI) is an orally potent tropomyosin receptor kinase (Trk) inhibitor that acts by competitive inhibition of all corresponding receptor kinases. It demonstrated a marked response rate (75%) and robust anticancer activity in Trk fusion-positive patients. This response is independent of cancer type, age and gender.Methods: In this study, an efficient and accurate LC-MS/MS analytical method was developed for Larotrectinib (LRB) quantification in addition to evaluation of its metabolic stability. LRB and lapatinib (LTP) (which is chosen as an internal standard; IS) were eluted utilizing an isocratic mobile phase with a reversed phase elution system (C 18 column).Results and Discussion: The linearity range of the established method was 5– 500 ng/mL (r 2 ≥ 0.9999) in the human liver microsomes (HLMs) matrix. Various parameters were calculated to validate the method sensitivity (limit of quantification was 5 ng/mL) and reproducibility (inter and intra-day accuracy and precision were below 3% in all samples) of our methodology. For evaluation of LRB metabolic stability in HLMs matrix, in vitro half-life (48.8 min) and intrinsic clearance (14.19 μL/min/mg) were computed.Conclusion: Accordingly, we can conclude that LRB is a moderate extraction ratio drug when compared with other tyrosine kinase inhibitors (TKIs). According to our knowledge, the discussed procedure in this study is the first LC-MS/MS analytical method for evaluating LRB metabolic stability.Keywords: larotrectinib, human liver microsomes, metabolic stability evaluation, tandem mass spectrometry |
| first_indexed | 2024-12-11T18:05:18Z |
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| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-11T18:05:18Z |
| publishDate | 2020-01-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-0092effb724d42f99ce7c3ae747b9ed22022-12-22T00:55:45ZengDove Medical PressDrug Design, Development and Therapy1177-88812020-01-01Volume 1411111951030Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass SpectrometryAttwa MWKadi AADarwish HWMohamed W Attwa, 1, 2 Adnan A Kadi, 1 Hany W Darwish 1, 3 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Students’ University Hospital, Mansoura University, Mansoura 35516, Egypt; 3Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptCorrespondence: Hany W Darwish Tel +966 1146 77343Fax +966 1146 76 220Email hdarwish@ksu.edu.saIntroduction: Larotrectinib (VITRAKVI) is an orally potent tropomyosin receptor kinase (Trk) inhibitor that acts by competitive inhibition of all corresponding receptor kinases. It demonstrated a marked response rate (75%) and robust anticancer activity in Trk fusion-positive patients. This response is independent of cancer type, age and gender.Methods: In this study, an efficient and accurate LC-MS/MS analytical method was developed for Larotrectinib (LRB) quantification in addition to evaluation of its metabolic stability. LRB and lapatinib (LTP) (which is chosen as an internal standard; IS) were eluted utilizing an isocratic mobile phase with a reversed phase elution system (C 18 column).Results and Discussion: The linearity range of the established method was 5– 500 ng/mL (r 2 ≥ 0.9999) in the human liver microsomes (HLMs) matrix. Various parameters were calculated to validate the method sensitivity (limit of quantification was 5 ng/mL) and reproducibility (inter and intra-day accuracy and precision were below 3% in all samples) of our methodology. For evaluation of LRB metabolic stability in HLMs matrix, in vitro half-life (48.8 min) and intrinsic clearance (14.19 μL/min/mg) were computed.Conclusion: Accordingly, we can conclude that LRB is a moderate extraction ratio drug when compared with other tyrosine kinase inhibitors (TKIs). According to our knowledge, the discussed procedure in this study is the first LC-MS/MS analytical method for evaluating LRB metabolic stability.Keywords: larotrectinib, human liver microsomes, metabolic stability evaluation, tandem mass spectrometryhttps://www.dovepress.com/metabolic-stability-assessment-of-larotrectinib-using-liquid-chromatog-peer-reviewed-article-DDDTlarotrectinibhuman liver microsomesmetabolic stability evaluationtandem mass spectrometry. |
| spellingShingle | Attwa MW Kadi AA Darwish HW Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry Drug Design, Development and Therapy larotrectinib human liver microsomes metabolic stability evaluation tandem mass spectrometry. |
| title | Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry |
| title_full | Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry |
| title_fullStr | Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry |
| title_full_unstemmed | Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry |
| title_short | Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry |
| title_sort | metabolic stability assessment of larotrectinib using liquid chromatography tandem mass spectrometry |
| topic | larotrectinib human liver microsomes metabolic stability evaluation tandem mass spectrometry. |
| url | https://www.dovepress.com/metabolic-stability-assessment-of-larotrectinib-using-liquid-chromatog-peer-reviewed-article-DDDT |
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