Influence of infusion duration on the pharmacokinetics (PK) of ifosfamide (IF) and metabolites

The anticancer prodrug IF requires activation through 4-hydroxylF (4OHIF) to ifosforamide mustard (IFM), to exert cytotoxicity. Deactivation of IF leads to 2- (2DCE) and 3-dechloroethylIF (3DCE) and the release of potentially neurotoxic chloroacetaldehyde. The PK of IF, 2DCE, 3DCE, 4OHIF and IFM in short (1-4 h), medium (24-72 h) and long infusion durations (96-240 h) of IF in 56 patients were compared using a population PK model with autoinduction. The rate by which autoinduction of the metabolism of IF developed and the fractions metabolized to 2DCE and 3DCE were found to be significantly dependent on the infusion schedule, but the differences were comparable to their interindividual variability and therefore not considered clinically relevant. During long infusion durations dose corrected exposures were significantly decreased for IF and increased for 3DCE. No differences in dose-normalized exposure to IF and metabolites were observed between short and medium infusion durations. Thus, the duration of IF infusion influences the exposure to IF and 3DCE. The dose and infusion duration dependency should be taken into account when the PD of different infusion schedules are evaluated.