Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin

Background. The autoinducible metabolic transformation of the anticancer ag ent ifosfamide involves activation through 4-hydroxyifosfamide to the ultim ate cytotoxic ifosforamide mustard and deactivation to 2- and. 3-dechloroet hylifosfamide with concomitant release of the neurotoxic chloroacetaldehyde . Activation is mediated by cytochrome P450 (CYP) 3A4 and deactivation by C YP3A4 and CYP2B6. The aim of this study was to investigate modulation of th e CY-P-mediated metabolism of ifosfamide with ketoconazole, a potent inhibi tor of CYP3A4, and rifampin (INN, rifampicin), an inducer of CYP3A4/CYP2B6. Methods. In a double-randomized, 2-way crossover study a total of 16 patien ts received ifosfamide 3 g/m(2) per 24 hours intravenously, either alone or in combination with 200 mg ketoconazole twice daily (1 day before treatmen t and 3 days of concomitant administration) or 300 mg rifampin twice daily (3 days before treatment and 3 days of concomitant administration). Plasma pharmacokinetics and urinary excretion of ifosfamide, 2- and 3-dechloroethy lifosfamide, and 4-hydroxyifosfamide were assessed in both courses. Data an alysis was performed with a population pharmacokinetic model with a descrip tion of autoinduction of ifosfamide. Results. Rifampin increased the clearance of ifosfamide at the start of the rapy at 102%. The fraction of ifosfamide metabolized to the dechloroethylat ed metabolites was increased, whereas exposure to the metabolites was decre ased as a result of increased elimination. The fraction metabolized and the exposure to 4-hydroxyifosfamide were not significantly influenced. Ketocon azole did not affect the fraction metabolized or the exposure to the dechlo roethylated metabolites, whereas both parameters were reduced with 4-hydrox yifosfamide. Conclusions. Coadministration of ifosfamide with ketoconazole or rifampin d id not produce changes in the pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamide therapy.