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- Title
Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients.
- Authors
Kerbusch, Thomas; van Putten, John W.; Groen, Harry J.; Huitema, Alwin D.; Mathôt, Ron A.; Beijnen, Jos H.; Kerbusch, T; vanPutten, J W; Groen, H J; Huitema, A D; Mathĵt, R A; Beijnen, J H
- Abstract
The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6. The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.
- Subjects
DRUG metabolism; PHARMACOKINETICS; PHARMACOLOGY; METABOLITES; BIOMOLECULES; LUNG cancer; ANTINEOPLASTIC agents; DRUG resistance in cancer cells; LUNG tumors; SMALL cell carcinoma; IFOSFAMIDE
- Publication
Cancer Chemotherapy & Pharmacology, 2001, Vol 48, Issue 1, p53
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s002800100277