Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites

This review discusses several issues in the clinical pharmacology of the an titumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied b y haematological toxicity, neurotoxicity and nephrotoxicity. Since its deve lopment in the middle of the 1960s, most of the extensive metabolism of ifo sfamide has been elucidated. Identification of specific isoenzymes responsi ble for ifosfamide metabolism may lead to an improved efficacy/toxicity rat io by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which ac tivated ifosfamide metabolites play a key role in this transport is current ly being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely und erstood. Assessment of the pharmacokinetics of ifosfamide and metabolites h as long been impaired by the lack of reliable bioanalytical assays. The rec ent development of improved bioanalytical assays has changed this dramatica lly, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences i n elimination dependent upon route and schedule of administration, implicat ions of the chirality pf the drug and interpatient pharmacokinetic variabil ity. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity a nd nephrotoxicity have been pivotal issues in the assessment of the pharmac odynamics of ifosfamide. Correlations between the new insights into ifosfam ide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisati on of ifosfamide treatment.