Oral and intravenous pharmacokinetics of 5-fluoro-2'-deoxycytidine and THU in cynomolgus monkeys and humans

Cancer Chemotherapy and Pharmacology
Julianne L HolleranJulie L Eiseman

Abstract

5-Fluoro-2'-deoxycytidine (FdCyd; NSC48006), a fluoropyrimidine nucleoside inhibitor of DNA methylation, is degraded by cytidine deaminase (CD). Pharmacokinetic evaluation was carried out in cynomolgus monkeys in support of an ongoing phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907). Animals were dosed intravenously (IV) or per os (PO). Plasma samples were analyzed by LC-MS/MS for FdCyd, metabolites, and THU. Clinical chemistry and hematology were performed at various times after dosing. A pilot pharmacokinetic study was performed in humans to assess FdCyd bioavailability. After IV FdCyd and THU administration, FdCyd C(max) and AUC increased with dose. FdCyd half-life ranged between 22 and 56 min, and clearance was approximately 15 mL/min/kg. FdCyd PO bioavailability after THU ranged between 9 and 25 % and increased with increasing THU dose. PO bioavailability of THU was less than 5 %, but did result in plasma concentrations associated with inhibition of its target CD. Human pilot studies showed comparable bioavailability for FdCyd (10 %) and THU (4.1 %). Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from <1 to 24 %. Con...Continue Reading

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Citations

Jul 28, 2016·Journal of Pharmaceutical and Biomedical Analysis·Julianne L HolleranJan H Beumer
Mar 21, 2017·Annals of Neurology·Carlos Lopez-GomezMichio Hirano
Apr 13, 2021·Journal of Biomedical Science·Kunal Nepali, Jing-Ping Liou
Nov 6, 2018·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Colin R YoungEsther Mena
May 26, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sarrah L HasanaliVinata B Lokeshwar
Sep 11, 2021·The Journal of Pharmacology and Experimental Therapeutics·William B Parker, Jaideep V Thottassery

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