Abstract 3782: Plasma pharmacokinetics of fluorodeoxycytidine, downstream metabolites, and tetrahydrouridine after combined administration to cynomolgus monkeys
Authors: Beumer Jan H. , Holleran Julianne L. , McCormick David L. , Johnson William D. , Covey Joseph M. , Davis Myrtle , Eiseman Julie L. 
Published: August 2012

Introduction: 5-Fluoro-2′-deoxycytidine (FdCyd; NSC48006) is a fluoropyrimidine nucleoside inhibitor of DNA methylation that is degraded by cytidine deaminase (CD) and has better aqueous stability than decitabine or azacytidine. A toxicokinetic study was carried out to support a phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907). We examined the pharmacokinetics of THU, FdCyd, and its downstream metabolites in cynomolgus monkeys. Methods: Monkeys were treated and plasma samples, collected between 15 min and 24 h after FdCyd administration, were analyzed. For IV administration, 20% of the THU dose was administered as a bolus followed by FdCyd (4, 8 or 16 mg/kg to two monkeys each) concomitantly with 80% of the THU dose of 30 mg/kg as a 3 h infusion. For PO administration, FdCyd was administered at 10 mg/kg as a single agent and at 10, 15 or 20 mg/kg 1 h after administration of 150 mg/kg THU or at 0.1, 1.0 or 10 mg/kg 1h after a dose of 500 mg/kg THU (2 monkeys/sex/group). The concentrations of FdCyd, and its downstream metabolites, fluorodeoxyuridine (FdUrd) and fluorouracil (FU), and THU were quantitated by validated LC-MS/MS assays. Data were modeled non-compartmentally using PK Solutions. Results: When FdCyd and THU were administered IV, FdCyd Cmax and AUC increased with dose, while the latter appeared more than dose-proportional. The half-life of FdCyd ranged between 22 and 56 min and the AUC0-inf increased from 0.28 to 2.99 mg·min/L after doses of 4 to 16 mg/kg. FdUrd/FdCyd Cmax and AUC0-infratios were less than 13% suggesting inhibition of CD at 30 mg/kg IV THU. In monkeys receiving 0.1 or 10 mg/kg FdCyd alone PO, no FdCyd nor any downstream metabolites were detectable. When FdCyd was administered 1 h after 150 or 500 mg/kg THU, PO FdCyd concentrations increased with doses of FdCyd. FdCyd PO bioavailability after THU appeared to range between 12 and 30% and did not clearly increase with increasing THU dose. FdUrd/FdCyd Cmax and AUC0-inf ratios after PO administration were higher than after IV administration and much more variable between monkeys. THU Cmax and AUC0-inf were proportional with THU dose and were not affected by FdCyd dose. PO bioavailability of THU was approximately 3.5%, but did result in plasma concentrations associated with inhibition of its target cytidine deaminase. Conclusion: Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from &lt;1% to &gt;12%. Concentrations of THU and FdCyd achieved after PO administration are associated with inhibition of CD and hypomethylation, respectively. The phase I study of PO FdCyd and THU is under development. Support: N01-CM-52202, N01-CM-42202, U01-CA099168, P30-CA47904

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3782. doi:1538-7445.AM2012-3782