Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

Purpose: In this study, pharmacokinetics (PK) of decitabine administered as a 3-h intravenous infusion of 15 mg/m² every 8 h for 3 days (cycles repeated every 6 weeks) was evaluated in patients with MDS or AML. Methods: The PK of this dosing regimen was evaluated in sixteen patients with MDS or AML. Plasma samples were obtained pre-dose and during the first 8-h dosing interval on each dosing day during Cycle 1, and at pre-dose and just prior to the end of infusion during Cycle 2. PK samples were assayed for decitabine by a sensitive and specific validated liquid chromatography-tandem mass spectrometry method. Results: The mean maximum observed plasma concentration (C _max), 64.8-77.0 ng/ml, and the mean area under the plasma concentration-time curve (AUC_0-∞), 152-163 ng h/ml, were unchanged during dosing of decitabine for 3 days. The time to the maximum concentration (T _max) generally occurred at the end of infusion. The mean values for terminal phase elimination half-life (0.62-0.78 h), total body clearance (125-132 l/h per m²), and volume of distribution at steady state (62.7-89.2 l/m ²), remained unchanged during the every 8 h dosing (P > 0.05). Cycles 1 and 2 C _max values for days 1, 2, and 3 were not significantly different as determined by paired two-tailed t test (P > 0.05). The primary toxicity of decitabine was myelosuppression, which was observed in all patients. Two deaths, from sepsis, were considered possibly related to decitabine. Conclusions: Decitabine dosed at 15 mg/m² iv every 8 h for 3 days resulted in a predictable and manageable toxicity profile in patients with MDS/AML. The repeated dosing did not result in systemic accumulation of the drug, and decitabine PK remained unchanged from cycle to cycle.