Population pharmacokinetics of ifosfamide and its dechloroethylated and hydroxylated metabolites in children with malignant disease - A sparse sampling approach

Objective: To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-de chloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with si ngle-agent ifosfamide against various malignant tumours. Design: Pharmacokinetic assessment followed by model fitting. Patients: The analysis included 32 patients aged between 1 and 18 years rec eiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m(2) in 1 or 3 hou rs on 1, 2 or 3 days. Methods: A total of 133 blood samples (median of 3 per patient) were collec ted. Plasma concentrations of ifosfamide and its dechloroethylated metaboli tes were determined by gas chromatography. Plasma concentrations of 4-hydro xyifosfamide were measured by high-performance liquid chromatography. The m odels were fitted to the data using a nonlinear mixed effects model as impl emented in the NONMEM program. ik cross-validation was performed. Results: Population values (mean standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/ h/m(2) and 20.6 +/- 1.6 L/m(2) with an interindividual variability of 43 an d 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h(2)/m(2). The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and t he elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hy droxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0 .0083 m(2)/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), re spectively. Interindividual variability of the first parameter was 23, 34 a nd 53%, respectively. Cross-validation indicated no bias and minor imprecis ion (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. Conclusions: We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse s ampling.