Pharmacokinetics of amsacrine in patients receiving combined chemotherapy for treatment of acute myelogenous leukemia

Summary

The pharmacokinetics of amsacrine have been studied after the first and third infusions (200 mg·m^-2) in 10 patients receiving combined chemotherapy for the treatment of acute myelogenous leukaemia (AML). Postinfusion amsacrine elimination was best described by a biexponential expression with a mean t_1/2α of 0.8 h and a terminal t_1/2β of 5.3 h. After the third infusion there was a significant reduction (P<0.05) in the plasma clearance (Cl) and a prolongation of the terminal half-life (t_1/2β) (P<0.01), but no change in the initial half-life (T_1/2α) or volume of distribution (Vd). No significant overall changes were recorded in any of the biochemical indices of renal or hepatic function between the first and third infusions, but the patient who exhibited the largest reduction in Cl showed a marked increase in AST levels and a reduction in albumin concentration. Two distinct groups were apparent after the first infusion, patients with a Cl>294 and those with a Cl<208 ml·h^-1·kg^-1. The latter patients were significantly older (P<0.05), and four of the five had subnormal albumin concentrations. Urinary determination of amsacrine indicated that renal elimination plays a minor role in the total clearance of this drug. Amsacrine was also found to be highly bound to plasma proteins (96.4%–97.7%), but changes in binding were not responsible for the reduced Cl and prolonged t_1/2β observed between the first and third infusions. We suggest that the elimination of amsacrine may be susceptible to small changes in hepatic function, perhaps due to the high amsacrine concentrations (5–18 μmol·l^-1) achieved with this regimen, which may be approaching saturation of the capacity for hepatic elimination.