Ribociclib is a selective, orally bioavailable inhibitor of cyclin-dependent kinase (CDK) 4/6, which has therapeutic potential for a variety of cancer types. This study was to develop and validate a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for determining total and unbound concentrations of ribociclib in human plasma and brain tumor tissue samples. Plasma and tumor homogenate samples were extracted using protein precipitation with acetonitrile. Unbound fraction in plasma or tumor homogenate was determined by equilibrium dialysis method. Chromatographic separation was achieved based on aqueous normal-phase chromatography mechanism on a Waters XBridge™ Amide column under isocratic elution with acetonitrile-ammonium formate (10 mM, pH 3) (75:25, v/v) at a flow rate of 0.8 mL/min. Ribociclib and the internal standard ([13C6]ribociclib) were monitored at the mass transitions m/z, 435.3 > 367.2 and 441.3 > 373.2, respectively, using positive electrospray ionization mode. The lower limit of quantitation (LLOQ) was 0.5 nM of ribociclib in plasma. Linear calibration curve was established at the concentration range of 0.5-1000 nM in plasma. Intra- and inter-day precision and accuracy were within the generally accepted criteria for bioanalytical method. The developed method was successfully applied to determine the plasma pharmacokinetics and central nervous system penetration of ribociclib in patients with malignant primary brain cancer.
Keywords: Aqueous normal-phase liquid chromatography; Blood-brain barrier; Liquid chromatography with tandem mass spectrometry (LC–MS/MS); Pharmacokinetics; Protein binding; Ribociclib.
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