Population Pharmacokinetics of Ifosfamide and its Dechloroethylated and Hydroxylated Metabolites in Children with Malignant Disease: A Sparse Sampling Approach

Authors: Kerbusch T.^{1, 2}; de Kraker J.³; Mathôt R.A.A.¹; Beijnen J.H.¹

Source: Clinical Pharmacokinetics, Volume 40, Number 8, 2001 , pp. 615-625(11)

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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-dechloroethyl-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/m 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/m and 20.6 ± 1.6 L/m with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 ± 0.0104 L/h/m. 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 m/L and 3.64 ± 2.04, 0.445 ± 0.174 and 7.67 ± 2.87 h, 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.

Keywords: Adolescents; Antineoplastics, pharmacokinetics; Children; Ifosfamide, pharmacokinetics; Infants

Language: English

Document Type: Original article

Affiliations: 1: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands 2: Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Uppsala, Uppsala, Sweden 3: Department of Paediatric Oncology, Academic Medical Centre, Amsterdam, The Netherlands *

Publication date: 2001-01-01

Population Pharmacokinetics of Ifosfamide and its Dechloroethylated and Hydroxylated Metabolites in Children with Malignant Disease: A Sparse Sampling Approach

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