title: Clinical pharmacology of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) following 72-hour infusion.
abstract: The clinical pharmacology of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine), a structural analogue of 1-beta-D-arabinofuranosylcytosine (ara-C) and 5-azacytidine, was assessed in 14 patients with various malignancies during a phase I trial. Since the starting dose for the protocol was low (0.2 mg/m2/hr over a 72-hr continuous iv infusion), a radioimmunoassay (RIA) using commercially available ara-C antibody and [3H]ara-C was developed to measure the anticipated low plasma drug levels. The assay could be used to measure fazarabine accurately in plasma and urine with a sensitivity of 0.08 ng/ml. The RIA does not require extraction of samples. Using both RIA and HPLC, similar results were obtained in plasma samples from a patient receiving a high dose (180 mg/m2/hr) of fazarabine. The assay is simple, sensitive, reproducible, and specific. Following the infusion, plasma levels declined triphasically with a terminal half-life of 5.7 +/- 2.0 hr. The AUC was linearly related to dose. When the various doses were normalized to 1.75 mg/m2/hr (the maximum tolerated dose as determined from the phase I trial) the mean AUC value was 4232 +/- 987 (ng/ml)hr. Plasma steady-state drug levels (CPss) were achieved in 2-4 hr and were linearly dependent to dose. Also, when normalized, the mean CPss was 58 +/- 13 ng/ml, which is within the reported concentration range necessary for inhibiting malignant cell growth. Total clearance was rapid, 528 +/- 138 ml/(m2.min), and not dose-related.
authors.affiliation: Division of Medicine, University of Texas M.D. Anderson Cancer Center.
authors.forename: D H
authors.initials: DH
authors.lastname: Ho
authors.forename: N
authors.initials: N
authors.lastname: Brown
authors.forename: J R
authors.initials: JR
authors.lastname: Lin
authors.forename: W
authors.initials: W
authors.lastname: Covington
authors.forename: R A
authors.initials: RA
authors.lastname: Newman
authors.forename: M
authors.initials: M
authors.lastname: Raber
authors.forename: R
authors.initials: R
authors.lastname: Amato
authors.forename: S
authors.initials: S
authors.lastname: Schmidt
authors.forename: I H
authors.initials: IH
authors.lastname: Krakoff
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D001374:Azacitidine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine / Q000031:analogs & derivatives; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; C022121:fazarabine; D001374:Azacitidine