Mohamed W Attwa1,2, Adnan A Kadi1, Hany W Darwish1,3. 1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. 2. Students' University Hospital, Mansoura University, Mansoura 35516, Egypt. 3. Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Abstract
INTRODUCTION: 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 (C18 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.
INTRODUCTION: 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 (C18 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.
Authors: Mohamed W Attwa; Adnan A Kadi; Hany W Darwish; Sawsan M Amer; Haitham Alrabiah Journal: Eur J Mass Spectrom (Chichester) Date: 2018-04-08 Impact factor: 1.067
Authors: R S Obach; J G Baxter; T E Liston; B M Silber; B C Jones; F MacIntyre; D J Rance; P Wastall Journal: J Pharmacol Exp Ther Date: 1997-10 Impact factor: 4.030
Authors: Robert C Doebele; Lara E Davis; Aria Vaishnavi; Anh T Le; Adriana Estrada-Bernal; Stephen Keysar; Antonio Jimeno; Marileila Varella-Garcia; Dara L Aisner; Yali Li; Philip J Stephens; Deborah Morosini; Brian B Tuch; Michele Fernandes; Nisha Nanda; Jennifer A Low Journal: Cancer Discov Date: 2015-07-27 Impact factor: 39.397