Population pharmacokinetics of ifosfamide and its 2-and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients

The aim of this study was to develop a population pharmacokinetic model tha t could describe the pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl ifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer rece ived a 1-h intravenous infusion of 2.0 or 3.0 g/m(2) ifosfamide over I or 2 days in combination with 175 mg/m(2) paclitaxel and carboplatin at AUC 6. The concentration-time profiles of ifosfamide were described by an ifosfami de concentration-dependent development of autoinduction of ifosfamide clear ance. Metabolite compartments were linked to the ifosfamide compartment ena bling description of the concentration-time profiles of 2- and 3-dechloroet hylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharma cokinetic parameters were used to calculate the systemic exposure to ifosfa mide and its metabolites for the four ifosfamide schedules. Fractionation o f the dose over 2 days resulted in increased metabolite formation, especial ly of 2-dechloroethylifosfamide, probably due to increased autoinduction. R enal recovery was only minor with 6.6% of the administered dose excreted un changed and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamid e pharmacokinetics were described with an ifosfamide concentration-dependen t development of autoinduction and allowed estimation of the population pha rmacokinetics of the metabolites of ifosfamide. Fractionation of the dose r esulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.