Pharmacokinetics, bioavailability and metabolism of CC-92480 in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry.

Abstract

CC-92480 is a cereblon E3 ubiquitin ligase modulating drug with potent antimyeloma activity. In this study, we developed a sensitive UHPLC-MS/MS method for the determination of CC-92480 in rat plasma. The plasma samples were prepared with acetonitrile and the samples were then separated on an Acquity BEH C18 column (2.1 × 50 mm, 1.7 μm) with water containing 0.1% formic acid (A) and acetonitrile (B) as mobile phase. The MS detection was performed using multiple reaction monitoring mode with precursor-to-product ion transitions at m/z 568.3 > 363.1 for CC-92480 and m/z 441.2 > 138.1 for ibrutinib (internal standard). The assay showed excellent linearity over the concentration range of 1-1,000 ng/ml, with correlation coefficient >0.995. The method was further validated for selectivity, precision, accuracy, recovery and stability according to the US Food and Drug Administration's guideline. The validated method was successfully applied to the pharmacokinetic and bioavailability studies of CC-92480 in rat plasma. Based on the pharmacokinetic results, the oral bioavailability of CC-92480 was >63%. In addition, the circulating metabolites of CC-92480 were detected by UHPLC-HRMS and the structures were proposed according to their accurate masses and fragment ions. The proposed metabolic pathways of CC-92480 were oxidative dealkylation and amide hydrolysis.