Dose-dependent pharmacokinetics of N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]-4-acridinecarboxamide (CI-921) in rabbits

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Abstract
N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]-4-acridinecarboxamide (CI-921), which is an analogue of amsacrine, has entered phase 1 clinical trials as an antitumour drug. The plasma pharmacokinetics of CI-921 has been studied in six rabbits after short i. v. infusions of 6.35, 12.7 and 25.4 μmol/kg. Total plasma concentrations of CI-921 were determined by a high-performance liquid chromatography method for up to 12 h post infusion. Comparison of pharmacokinetic parameters for each rabbit by within-subject analysis of variance indicated that with a four-fold increase in the dose from 6.35 to 25.4 μmol/kg there was a 44% increase in the area under the concentration-time curve normalised to dose (P(0.001) and a 43% increase in the elimination half-life (P(0.005), and a 30% decrease in the total plasma clearance (P(0.001). Dose had no effect on the end of infusion concentration normalised to dose, or on the steadystate volume of distribution. These results indicate that CI-921 experiences dose-dependent elimination kinetics in the rabbit.