Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
OBJECTIVE
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 (Cmax), 64.8-77.0 ng/ml, and the mean area under the plasma concentration-time curve (AUC0-infinity), 152-163 ng h/ml, were unchanged during dosing of decitabine for 3 days. The time to the maximum concentration (Tmax) 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/m2), remained unchanged during the every 8 h dosing (P>0.05). Cycles 1 and 2 Cmax 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.
Cashen
Amanda F
AF
Department of Medicine, Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8007, St. Louis, MO 63110, USA. acashen@im.wustl.edu
Shah
Ajit K
AK
Todt
Laura
L
Fisher
Nicholas
N
DiPersio
John
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001374:Azacitidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D000077209:Decitabine; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D018805:Sepsis / Q000209:etiology; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine