Abstract
Spebrutinib (SBT) is a Bruton's tyrosine kinase inhibitor. SBT is currently in phase II and phase I clinical trials for the management of rheumatoid arthritis and chronic lymphocytic leukaemia, respectively. We developed and validated a liquid chromatography tandem mass spectrometry analytical method to quantify SBT and investigate its metabolic stability. SBT and the naquotinib as internal standard were isocratically eluted on a C18 column. The linearity of the developed method is 5–500 ng ml−1 (r2 ≥ 0.9999) in the human liver microsomes (HLMs) matrix. Good sensitivity was approved by the very low limit of detection (0.39 ng ml−1). Inter- and intra-assay accuracy values of −1.41 to 12.44 and precision values of 0.71% to 4.78%, were obtained. SBT was found to have an in vitro half-life (82.52 min) and intrinsic clearance (8.4 µl min−1 mg−1) as computed following its incubation with HLMs. The latter finding, hypothesize that SBT could be slowly excreted from the body unlike other related tyrosine kinase inhibitors. So, drug plasma level and kidney function should be monitored because of potential bioaccumulation. To the best of our knowledge, this is considered the first analytical method for SBT quantification using LC-MS/MS with application to metabolic stability evaluation.
Highlights
Bruton’s tyrosine kinase (BTK) has recently become a promising drug target for many diseases, especially haematopoietic malignancies and autoimmune diseases associated with B lymphocytes
We developed and validated a liquid chromatography tandem mass spectrometry analytical method to quantify SBT and investigate its metabolic stability
Acalabrutinib is a BTK inhibitor established by Acerta Pharma and has been approved by the Food and Drug Administration (FDA) for adult patients with mantle cell lymphoma who have received at least one prior therapy [1]
Summary
Bruton’s tyrosine kinase (BTK) has recently become a promising drug target for many diseases, especially haematopoietic malignancies and autoimmune diseases associated with B lymphocytes. Many BTK inhibitors are currently in different stages of clinical trials. SBT irreversibly and covalently binds to BTK leading to B cell receptor (BCR) signalling. It inhibits malignancies associated with B cell proliferation. SBT, established by Avila Therapeutics (acquired by Celgene in March 2012), is currently in phase II clinical trials for rheumatoid arthritis and offers an encouraging future for the management of leukaemia and autoimmune diseases. It is in phase I trials for chronic lymphocytic leukaemia (CLL). In 2014, Orphan Drug Designation was designated in the EU for the cure of CLL [2,3,4,5]
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