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Pediatric Development of Bosentan Facilitated by Modeling and Simulation

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Abstract

Background

Bosentan is approved for use in adult patients with pulmonary arterial hypertension. The primary aim of the pharmacokinetic modeling was the provision of a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range.

Methods

A physiologically based pharmacokinetic model was developed for the pediatric population; starting from an adult model, the effects of body weight, age, and maturation of relevant metabolizing enzymes were incorporated to extrapolate the pharmacokinetics to children. A pediatric population pharmacokinetic model was developed to identify relevant covariates.

Results

Based on model predictions, a dose of 0.5 mg/kg led to an exposure distinguishable from a dose of 2 mg/kg, and an additional blood sampling time point at 2 h (the predicted time of maximum concentration) allowed more precise estimation of bosentan exposure in children. The lower exposure observed in children compared with adults could be explained by maturation-related changes in clearance. Clinical data confirmed the model predictions.

Conclusions

Maturational changes in drug clearance and developmental changes in body weight were identified as key elements of bosentan pharmacokinetics in pediatric patients. Estimating bosentan exposure using physiologically based and population pharmacokinetic modeling and simulation supported dose selection in pediatric patients. Model-based exposure estimates helped in reducing the number of the youngest pediatric patients to be studied. Pharmacokinetic models can provide a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range.

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Acknowledgements

We thank Laurent Nicolas (Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) for his contributions to the protocol design of FUTURE-3, -4, and -5 and Michael Block and Stefan Willmann (BTS, Leverkusen, Germany) for their contributions to the PBPK modeling work. We thank the clinical teams and all patients and parents involved in the conduct of the clinical studies that helped determine appropriate doses of bosentan for pediatric patients.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Jochen Zisowsky, Martine Géhin, Andreas Krause & Jasper Dingemanse

  2. Department of Clinical Science and Epidemiology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Andjela Kusic-Pajic

  3. Pediatric Subspecialties Division and Pediatric Cardiology Unit, Children’s University Hospital, Rue Gabrielle-Perret 4, 1205, Geneva, Switzerland

    Maurice Beghetti

Authors
  1. Jochen Zisowsky
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  2. Martine Géhin
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  3. Andjela Kusic-Pajic
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  4. Andreas Krause
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  5. Maurice Beghetti
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  6. Jasper Dingemanse
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Corresponding author

Correspondence to Jasper Dingemanse.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included.

Funding

All studies were funded by Actelion Pharmaceuticals Ltd. JZ, MG, AKP, AK, and JD were employees of Actelion Pharmaceuticals Ltd at the time of study conduct and analysis. MB consults for Actelion Pharmaceuticals Ltd.

Conflict of interest

JZ, MG, AKP, AK, and JD were employees of Actelion Pharmaceuticals Ltd at the time of study conduct and analysis. MB consults for Actelion Pharmaceuticals Ltd.

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Zisowsky, J., Géhin, M., Kusic-Pajic, A. et al. Pediatric Development of Bosentan Facilitated by Modeling and Simulation. Pediatr Drugs 19, 121–130 (2017). https://doi.org/10.1007/s40272-016-0206-0

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