Ifosfamide has been shown to require metabolic activation by microsomal liver enzymes to produce biologically active metabolites. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. Opening of the ring results in formation of the stable urinary metabolite, 4-carboxyifosfamide. These urinary metabolites have not been found to be cytotoxic. N, N- bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation produces the major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide. The alkylated metabolites of ifosfamide have been shown to interact with DNA.
In vitro incubation of DNA with activated ifosfamide has produced phosphotriesters. The treatment of intact cell nuclei may also result in the formation of DNA-DNA cross-links. DNA repair most likely occurs in G-1 and G-2 stage cells.
Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8-5.0 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6-2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours. Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses.
After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6-2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.
Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present. Small quantities (nmole/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.
In a study at Indiana University, 50 fully evaluable patients with germ cell testicular cancer were treated with IFEX in combination with cisplatin and either vinblastine or etoposide after failing (47 of 50 patients) at least two prior chemotherapy regimens consisting of cisplatin/vinblastine/bleomycin, (PVB), cisplatin/vinblastine/actinomycin D/bleomycin/cyclophosphamide, (VAB6), or the combination of cisplatin and etoposide. Patients were selected for remaining cisplatin sensitivity because they had previously responded to a cisplatin containing regimen and had not progressed while on the cisplatin containing regimen or within 3 weeks of stopping it. Patients served as their own control based on the premise that long term complete responses could not be achieved by retreatment with a regimen to which they had previously responded and subsequently relapsed.
Ten of 50 fully evaluable patients were still alive 2 to 5 years after treatment. Four of the 10 long term survivors were rendered free of cancer by surgical resection after treatment with the ifosfamide regimen; median survival for the entire group of 50 fully evaluable patients was 53 weeks.