Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: Implications for a continuous infusion schedule

Abstract

Arabinosylcytosine (ara-C) is a cytotoxic agent with major activity against acute leukemias. To exert this effect, it must first be phosphorylated to its active 5'-triphosphate, ara-CTP, which is incorporated into DNA. Our previous studies demonstrated that preincubation with arabinosyl-2-fluoroadenine (F-ara-A) increased the rate of ara-CTP accumulation in leukemia cells when incubated with 10 μM ara-C. Such concentrations of ara-C are readily obtained during intermittent bolus infusions of ara-C, and clinical trials were conducted using fludarabine in combination with 2-h infusions of intermediate dose ara-C. During continuous infusion of ara-C, however, serum ara-C levels are < 10 μM. Bec..