Clinical Pharmacokinetics and Pharmacodynamics of Ifosfamide and its Metabolites

Abstract

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

Enantioselective liquid chromatography–mass spectrometry assay for the determination of ifosfamide and identification of the N-dechloroethylated metabolites of ifosfamide in human plasma

“…The samples were analyzed as part of the protocol "The relationship of cytochrome P450 3A4 and cytochrome P450 2B6 to the therapeutic index of high-dose intravenous ifosfamide" (NIA Protocol # 2003-117). After obtaining informed consent, venous blood samples (7 ml) were collected using heparinized vacutainer tubes at 0 (predose) and 3,6,12,18,24,30,36,48,72 and 96 h during the infusion and 0, 2, 4, 6, 12, 18 and 24 h post-infusion.…”

“…The hepatic metabolism of IF has been extensively studied and occurs in the liver by two major pathways, Fig. 1 [6][7][8][9][10][11]. One pathway involves the 4-hydroxylation of IF and eventually leads to the production of the cytotoxic isophosphoramide mustard [6].…”

“…1 [6][7][8][9][10][11]. One pathway involves the 4-hydroxylation of IF and eventually leads to the production of the cytotoxic isophosphoramide mustard [6]. The 4-hydroxylation of R-IF is catalyzed by CYP3A4 and the 4-hydroxylation of S-IF by CYP2B6 [10,11].…”

Phase I and pharmacokinetic study of the combination of topotecan and ifosfamide administered intravenously every 3 weeks

“…It is also used to treat cancers of the head and neck, breast, cervix, ovaries, soft tissue sarcoma, Ewing's sarcoma, osteosarcoma, both Hodgkin's and non-Hodgkin's lymphomas, non-smallcell lung cancer, acute lymphocytic leukaemia, and neuroblastoma (Kerbusch et al, 2001a). Ifosfamide is a prodrug, which needs to undergo activation by cytochrome P450-3A4 (CYP3A4) to 4-hydroxyifosfamide (4OHIF).…”

“…It was proposed that DNA alkylation triggers DNA repair mechanisms, which may depend on topoisomerase-I. Ifosfamide was chosen as representative alkylator because it is associated with less haematological toxicity than cyclophosphamide (Kerbusch et al, 2001a).…”