Phase I clinical and pharmacokinetic study of N4-behenoyl-1-beta-D-arabinofuranosylcytosine.
A phase I study of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC) was conducted in 66 patients, 41 with solid tumors and 25 with hematological malignancies. The patients received either a 2-h single intravenous (i.v.) drip infusion (Schedule 1) or consecutive daily 2-h i.v. infusions (Schedule 2). In Schedule 1 the daily dose was initiated with 1.5 mg kg-1 which was escalated up to 7 mg kg-1. Side-effects were mild, and included nausea, vomiting, epilation, and hot flushes. Because of the presence of the solvent vehicle, HCO-60 and in consideration of the mechanism of action of BHAC, the dose escalation was stopped at 7 mg kg-1. In Schedule 2, the daily dose was started with 1.5 mg kg-1 which was escalated up to 8 mg kg-1 and given for 2-16 days. Myelosuppression was found to be dose-limiting toxicity. The maximum tolerated dose (MTD) in patients with non-hematological solid tumors was assumed to be 5 mg kg-1 daily X 5 days. The plasma disappearance curve of BHAC looked biphasic, and when 4 mg kg-1 of BHAC were administered the half-lives of the initial phase (t1/2 alpha) and the second phase (t1/2 beta) were calculated as 0.798 and 5.76 h respectively. In Schedule 2 complete remission was observed in 5 out of 21 patients with acute leukemia, one partial remission in Hodgkin's disease, and one 1-B response (Karnofsky) in thyroid papillary adenocarcinoma.
Kimura
K
K
Ohno
R
R
Amaki
I
I
Hattori
K
K
Hirota
Y
Y
Hoshino
A
A
Ichimaru
M
M
Ito
M
M
Kimura
I
I
Maekawa
T
T
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism*; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004361:Drug Tolerance; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged
D000970:Antineoplastic Agents; D003561:Cytarabine; C015019:enocitabine