Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients.
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.
Kerbusch
T
T
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam. Thomas.Kerbusch@biof.uu.se
vanPutten
J W
JW
Groen
H J
HJ
Huitema
A D
AD
Mathĵt
R A
RA
Beijnen
J H
JH
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
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide