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-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours.


METHODS
Pharmacokinetic assessment followed by model fitting.


METHODS
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.


METHODS
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.


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/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.


CONCLUSIONS
We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.
Kerbusch
T
T
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam. Thomas.Kerbusch@biof.uu.se
de Kraker
J
J
Mathĵt
R A
RA
Beijnen
J H
JH
D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide