A Phase I Pharmacokinetic Trial of Decitabine Administered as a 3-Hour Infusion to Patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS).

Background: Decitabine (Dacogen^TM) is a cytosine analogue that promotes hypomethylation of DNA. Although decitabine has been extensively studied in Phase II and III trials in patients with MDS, relatively limited pharmacokinetic (PK) data is available in this patient population. Recently, a Phase III trial of decitabine in advanced MDS demonstrated that decitabine administered as a 3-hour infusion of 15 mg/m² every 8 hours for 3 days (cycles repeated every 6 weeks) results in a significantly higher response rate and improves time to AML or death compared to best supportive care (

Methods: The PK of this dosing regimen was evaluated in twelve patients (8M/4F, age 50–87 yr) with MDS (n=6, IPSS ≥ 1.5) or relapsed/refractory AML (n=6). Patients were treated with the same dose and schedule as the Phase III trial, with a second cycle repeated six weeks after the first. Plasma samples were obtained pre-dose and during the first 8-hour 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 LC/MS/MS method.

Results: Day 1 cycle 1 PK results (mean±SD) from ten patients are shown in the table below (data from two patients excluded due to dosing error).

In plasma, decitabine did not accumulate during three days of dosing, and CLp remained unchanged. For the 5 patients who have received decitabine for two cycles, C_max values for cycle 1 (49.0±22.2 ng/mL) and cycle 2 (62.7±45.2) were comparable, indicating unchanged PK during both cycles. This regimen of decitabine was generally well-tolerated. Serious adverse events included neutropenia and fever (2 patients) and infection (one patient with gram positive bacteremia and pneumonia). In addition, one patient died of sepsis, and two died of progressive AML. Of four patients who have been assessed for response after 2 cycles of decitabine, one patient with MDS had a complete response, one patient with MDS had hematologic improvement, and two patients (one MDS, one AML) had no response.

Conclusions: We conclude that repeated administration of decitabine does not result in systemic accumulation of the drug, and PK remains unchanged from cycle to cycle. It will be of interest in future studies to correlate pharmacokinetics of decitabine with pharmacodynamic changes in CpG island methylation and clinical responses.