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Title: Pharmacological studies of ifosfamide
Author: Highley, Martin Steven
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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The plasma pharmacokinetics and neurotoxicity of oral ifosfamide were studied in seven females with carcinoma of the cervix and four males with non-small cell lung cancer. The median age was 58 years (range 33-70). Oral ifosfamide was administered at a dose of 500 mg twice daily for 14 days; 300 mg of mesna was given twice daily concurrently for uroprotection. Gas chromatography - mass spectrometry was used to analyse ifosfamide and seven of its metabolites; isophosphoramide mustard, 2-and 3-dechloroethylifosfamide, carboxyifosfamide, ketoifosfamide, chloroethylamine, and 1, 3-oxazolidine-2-one. The basic metabolites chloroethylamine and 1, 3-oxazolidine-2-one, predicted from the metabolism of cyclophosphamide, have not been described previously in biological fluids. Ifosfamide neurotoxicity was assessed using the electroencephalogram, psychometric testing, the national adult reading test, the mini-mental state examination, and clinical evaluation of symptoms. The mean Cmax, and AUC to eight hours, of ifosfamide were less on day 14, but not significantly so. Ifosfamide Cmax was 53.1 μM (SD ± 18.5) on day 1, and 50.7 μM (SD ± 25.8) on day 14. Corresponding values for the AUC to eight hours were 293 μM. hr (SD ± 67), and 256 μM. hr (SD ± 118). It was not possible to estimate the AUC to eight hours accurately, on account of the twice daily dosage regimen. The mean absorption rate constant of ifosfamide on day 1 was 1.23 hr-1 (SD ± 1.01). The Cmax of most ifosfamide metabolites increased on day 14, particularly ketoifosfamide, 2- and 3- dechloroethylifosfamide, carboxyifosfamide and 1, 3-oxazolidine-2-one, whereas that of isophosphoramide mustard was unchanged. Decreased alpha frequency was seen in the electroencephalogram, with the development of pathological slow wave activity. Psychometric performance was also impaired. All patients developed a feeling of detachment or an inability to concentrate, and two suffered hallucinations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available