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

• Published in: Clinical pharmacokinetics 2001, Vol.40 (8), p.615-625
• Main Authors: KERBUSCH, Thomas, DE KRAKER, Jan, MATHOT, Ron A. A, BEIJNEN, Jos H
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antineoplastic agents; Antineoplastic Agents, Alkylating - metabolism; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - therapeutic use; Area Under Curve; Biological and medical sciences; Chemotherapy; Child; Child, Preschool; Feasibility Studies; Female; Humans; Ifosfamide - metabolism; Ifosfamide - pharmacokinetics; Ifosfamide - therapeutic use; Infant; Male; Medical sciences; Metabolic Clearance Rate; Models, Biological; Neoplasms - drug therapy; Pharmacology. Drug treatments
• ISSN: 0312-5963; 1179-1926
• DOI: 10.2165/00003088-200140080-00005

To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours. Pharmacokinetic assessment followed by model fitting. The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m2 in 1 or 3 hours on 1, 2 or 3 days. A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy-ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. Population values (mean +/- standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/h/m2 and 20.6 +/- 1.6 L/m2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h2/m2. The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0.0083 m2/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.