Pharmacokinetic assessment of low dose decitabine in combination therapies: Development and validation of a sensitive UHPLC-MS/MS method for murine plasma analysis.

• A sensitive method for quantifying decitabine in mouse plasma was developed and validated. • Robust, accurate, and precise results were demonstrated, with a lower limit of quantitation of 0.4 ng/mL. • Decitabine was determined in microvolumes of mouse plasma. • Increased oral bioavailability of decitabine was observed when given with cedazuridine. • The mouse model was found useful for evaluating pharmacokinetic drug-drug interactions with decitabine. Decitabine is a DNA methyltransferase inhibitor used in the treatment of acute myeloid leukemia and myelodysplastic syndrome. The notion that ongoing trials are presently exploring the combined use of decitabine, with or without the cytidine deaminase inhibitor cedazuridine, and other antileukemic drugs necessitates a comprehensive understanding of pharmacokinetic properties and an evaluation of drug-drug interaction liabilities. We report here the development and validation of a sensitive UHPLC-MS/MS method for quantifying decitabine in mouse plasma, which should be useful for such studies. The method involved a one-step protein precipitation extraction, and chromatographic separation on an XBridge HILIC column using gradient elution. The method was found to be robust, accurate, precise, and sufficiently sensitive (lower limit of quantitation, 0.4 ng/mL) to determine decitabine concentrations in microvolumes of plasma from mice receiving the agent orally or intravenously in the presence or absence of cedazuridine. [ABSTRACT FROM AUTHOR]