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Population Pharmacokinetics of Ifosfamide and its Dechloroethylated and Hydroxylated Metabolites in Children with Malignant Disease

A Sparse Sampling Approach

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Abstract

Objective

To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloro-ethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-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 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.

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Acknowledgements

No financial relationships with commercial companies were involved in this study.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands

    Thomas Kerbusch, Ron A. A. Mathôt & Jos H. Beijnen

  2. Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Uppsala, BMC Box 591, S-751 24, Uppsala, Sweden

    Thomas Kerbusch

  3. Department of Paediatric Oncology, Academic Medical Centre, Amsterdam, The Netherlands

    Jan de Kraker

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  1. Thomas Kerbusch
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  2. Jan de Kraker
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  4. Jos H. Beijnen
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Correspondence to Thomas Kerbusch.

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Kerbusch, T., de Kraker, J., Mathôt, R.A.A. et al. Population Pharmacokinetics of Ifosfamide and its Dechloroethylated and Hydroxylated Metabolites in Children with Malignant Disease. Clin Pharmacokinet 40, 615–625 (2001). https://doi.org/10.2165/00003088-200140080-00005

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