The clinical pharmacokinetics of N-5-dimethyl-9-[(2-methoxy-4-methyl-sulfonylamino)phenylamino]-4 -acridinecarboxamide (CI-921) in a phase 1 trial.
The pharmacokinetics of CI-921 were studied after 65 infusions over a 20-fold dose range (13-270 mg/m2 per day) in 16 patients during a phase 1 trial. CI-921 was given by a 15 min infusion on three consecutive days. Plasma samples were collected after the first and third infusions, and urine, at 6 h intervals throughout the 3 days. CI-921 concentrations were measured by an HPLC method. Maximum plasma concentrations ranged from 3-86 mumol/l. The plasma concentration-time disposition curves were mainly biphasic over the 24-h postinfusion period. There was no significant difference by the paired t-test between the Cmax, AUC, CL, Vss, MRT, t1/2 alpha, or t1/2 beta calculated for the first and third infusions. The means (range) of model-independent pharmacokinetic parameters were: CL, 158 (94-290) ml/h per kg; Vss, 319 (219-614) ml/kg; MRT, 2.1 (1.1-3.5) h; t1/2 alpha, 0.5 (0.2-1.1) h; and t1/2 beta, 2.6 (1.1-5.0) h. There was a strong linear correlation between the dose and the AUC and Cmax, suggesting linear kinetics over this dose range. A very small amount (less than 1%) of the total dose was excreted as unchanged CI-921 in the urine, mostly in the 12-h postinfusion period.
Paxton
J W
JW
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
Hardy
J R
JR
Evans
P C
PC
Harvey
V J
VJ
Baguley
B C
BC
D000328:Adult; D000368:Aged; D000677:Amsacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged
D000970:Antineoplastic Agents; D000677:Amsacrine; C042315:asulacrine