Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

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Serval ID
serval:BIB_8B0BBA7542AB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).
Journal
Annals of Oncology
Author(s)
Cerny T., Leyvraz S., von Briel T., Küpfer A., Schaad R., Schmitz S.F., Honegger P., Sessa C., Brunner J., Boddy A.V.
ISSN
0923-7534 (Print)
ISSN-L
0923-7534
Publication state
Published
Issued date
1999
Volume
10
Number
9
Pages
1087-1094
Language
english
Abstract
BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas.
PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed.
RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%).
CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.
Keywords
Adult, Aged, Antineoplastic Agents, Alkylating/blood, Antineoplastic Agents, Alkylating/pharmacokinetics, Area Under Curve, Dose-Response Relationship, Drug, Female, Granulocyte-Macrophage Colony-Stimulating Factor/pharmacokinetics, Humans, Ifosfamide/blood, Ifosfamide/pharmacokinetics, Male, Mesna/pharmacokinetics, Mesna/toxicity, Middle Aged, Prodrugs/pharmacokinetics, Protective Agents/pharmacokinetics, Protective Agents/toxicity, Remission Induction, Sarcoma/drug therapy, Time Factors
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 14:11
Last modification date
25/09/2019 7:09
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