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Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children

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Abstract

Purpose

To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data.

Methods

Simulations were performed with PK-Sim® (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis–Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group.

Results

Simulated plasma concentration–time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70 ml/min/kg (Clobserved: 0.70 ml/min/kg) versus 0.50 ml/min/kg (Clobserved: 0.60 ml/min/kg), respectively. Integrated Michaelis–Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P-glycoprotein inhibitors or nephrotoxic drugs can also be elucidated.

Conclusions

The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children.

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Acknowledgments

The centre for clinical trials is funded by the German Federal Office for Research and Technology (BMBF, 01KN0705). This work was supported by Bayer Technology Services GmbH.

Conflict of interest

Stefan Willmann and Jörg Lippert are employees of Bayer Technology Services. Georg Hempel and Gisela Kersting received funding from Bayer Technology Services.

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Authors and Affiliations

  1. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Münster, Germany

    Gisela Kersting & Georg Hempel

  2. Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Münster, Germany

    Gisela Kersting, Joachim Boos & Georg Hempel

  3. Bayer Technology Services GmbH, Competence Centre Systems Biology and Computational Solutions, 51368, Leverkusen, Germany

    Stefan Willmann & Jörg Lippert

  4. Centre for Clinical Trials, University of Münster, Münster, Germany

    Gudrun Würthwein

  5. Institut für Pharmazeutische und Medizinische Chemie—Klinische Pharmazie, Westfälische Wilhelms-Universität Münster, Hittorfstr. 58-62, 48149, Münster, Germany

    Georg Hempel

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  1. Gisela Kersting
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  2. Stefan Willmann
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Correspondence to Georg Hempel.

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Kersting, G., Willmann, S., Würthwein, G. et al. Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children. Cancer Chemother Pharmacol 69, 397–405 (2012). https://doi.org/10.1007/s00280-011-1706-9

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  • DOI: https://doi.org/10.1007/s00280-011-1706-9

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