title: Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients.
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.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam. Thomas.Kerbusch@biof.uu.se
authors.forename: T
authors.initials: T
authors.lastname: Kerbusch
authors.forename: J W
authors.initials: JW
authors.lastname: vanPutten
authors.forename: H J
authors.initials: HJ
authors.lastname: Groen
authors.forename: A D
authors.initials: AD
authors.lastname: Huitema
authors.forename: R A
authors.initials: RA
authors.lastname: Mathĵt
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000493:pharmacokinetics*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide