ABSTRACT
No abstract available.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Nevus, PigmentedABSTRACT
This study describes the development of an analytical method to determine radotinib levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) for pharmacokinetic application. Plasma samples were sequentially processed by liquid-liquid extraction using methyl tert-butyl ether, evaporation, and reconstitution. Analytes were separated and analyzed using HPLC-MS/MS in selected reaction monitoring mode, monitoring the specific transitions of m/z 531 to 290 for radotinib and m/z 409 to 238 for amlodipine (internal standard). The HPLC-MS/MS analytical method was validated with respect to selectivity, linearity, sensitivity, accuracy, precision, recovery, and stability. Calibration curves were linear over a concentration range 5–3,000 ng/mL with correlation coefficients (r) > 0.998. The lower limit of quantification for radotinib in plasma was 5 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. This method was suitable to determine radotinib levels in human plasma because of its simplicity, selectivity, precision, and accuracy.
Subject(s)
Humans , Amlodipine , Calibration , Chromatography, Liquid , Ether , Liquid-Liquid Extraction , Mass Spectrometry , Methods , Plasma , Quality Control , Tandem Mass SpectrometryABSTRACT
The clinical outcome for patients with chronic myeloid leukemia (CML) has improved radically in the past 15 years. Imatinib led to high rates of complete cytogenetic responses and improved survival for patients with this disease. However, approximately 25-35% of patients in chronic phase treated with imatinib developed treatment failure. Development of next-generation Tyrosine kinase inhibitors (TKIs), such as dasatinib, nilotinib, radotinib, bosutinib, and ponatinib, has provided new therapeutic option for the patients resistant or intolerant to imatinib. Second generation (2G) TKIs were active in most clinically relevant BCR-ABL mutations, except highly resistant T315I. Through the phase 3 international randomized studies of 2G TKIs (dasatinib, nilotinib, and bosutinib) vs. imatinib, 2G TKIs emerged as the standard treatment for CML and have successfully prolonged the duration of both the chronic phase (CP) and the disease-free state. The majority of newly diagnosed patients treated with 2G TKIs achieved a complete cytogenetic response (CCyR), and over time, most of these eventually achieved major molecular responses (MMRs) and even complete molecular responses (CMRs). More recently, both dasatinib and nilotinib were approved for frontline use, and dasatinib, nilotinib, radotinib and bosutinib were approved for second-line use in patients with CML. Ponatinib represents the third generation of TKI, and this drug has been developed with the aim of targeting a specific BCR-ABL1 mutation (T315I), which arises in the setting of prolonged TKI therapy and leads to resistance to all commercially available TKIs.