Plasma pharmacokinetics of N -[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial

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Abstract
DACA {N-[2-(dimethylamino)ethyl]acridine-4-carboxamide} is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m2 (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m2. Drug was given by constant intravenous infusion with a target delivery period of 3 h. Blood samples were taken from the contralateral arm before, during and for up to 72 h after the infusion. DACA was separated from plasma by solid-phase extraction and was analysed by reversed-phase high-performance liquid chromatography (C18 column) using fluorescence detection. A two-compartment pharmacokinetic model provided the best fit for the concentration-time profiles obtained for most patients showing clearance of 1.00 ± 0.36 l h−1 kg−1, a volume of distribution of the central compartment of 0.72 ± 0.55 l/kg, an initial half-life of 0.28 ± 0.19 h and a terminal half-life of 2.04 ± 0.94 h. All pharmacokinetic parameters were independent of dose, indicating first-order kinetics. As DACA binds strongly to α1-acid glycoprotein, plasma concentrations of this protein were determined and used to estimate free-drug fractions in plasma. Estimated values for the free fraction varied from 0.9% to 3.3% and were lower than those determined by equilibrium dialysis for mice and rats (15% and 16%, respectively). At the maximum tolerated dose (MTD) of 750 mg/m2, the area under the drug concentration-time curve (AUC) was 46.2 ± 4.4 μM h, exceeding that obtained in mice treated at the MTD (23.4 μM h). On the other hand, the corresponding free-drug AUC was 0.92 ± 0.03 μM h, much lower than the corresponding value (3.5 μM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction.

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